Dana Cramariuc

Low-Flow Aortic Stenosis in Asymptomatic Patients: Valvular–Arterial Impedance and Systolic Function From the SEAS Substudy

OBJECTIVES This study sought to assess the impact of valvuloarterial impedance on left ventricular (LV) myocardial systolic function in asymptomatic aortic valve stenosis (AS). BACKGROUND In atherosclerotic AS, LV global load consists of combined valvular and arterial resistance to LV ejection. Global load significantly impacts LV ejection fraction (EF) in symptomatic AS, but less is known about its effect on LV myocardial function in asymptomatic AS. METHODS Echocardiograms in 1,591 patients with asymptomatic AS (67 +/- 10 years, 51% hypertensive) at baseline in the SEAS (Simvastatin Ezetimibe in Aortic Stenosis) study evaluating placebo-controlled combined simvastatin and ezetimibe treatment in AS were used to assess LV global load as valvuloarterial impedance and LV myocardial function as stress-corrected midwall shortening. The study population was divided into tertiles of global load. Stress-corrected midwall shortening was considered low if <87% in men and <90% in women. Low-flow AS was defined as stroke volume index <22 ml/m(2.04). RESULTS Energy loss index decreased (0.85 cm(2)/m(2) vs. 0.77 and 0.75 cm(2)/m(2)) and the prevalence of low stress-corrected midwall shortening increased (10% vs. 26% and 63%) with increasing LV global load (all p < 0.001). The EF was low in only 2% of patients. Patients with low-flow AS had higher LV global load and more often low midwall shortening than those with normal-flow AS (9.66 +/- 2.23 mm Hg/ml.m(2.04) and 77%, vs. 6.38 +/- 2.04 mm Hg/ml.m(2.04) and 30%, respectively, p < 0.001). In logistic regression analysis, LV global load was a main predictor of low stress-corrected midwall shortening independent of male sex, concentric LV geometry, LV hypertrophy (all p < 0.001), concomitant hypertension, and aortic regurgitation. CONCLUSIONS LV global load impacts LV myocardial function in asymptomatic AS independent of other main covariates of LV systolic function. LV myocardial systolic dysfunction is common in asymptomatic AS in particular in patients with low-flow AS and increased valvuloarterial afterload, whereas EF is generally preserved. (An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis [Narrowing of the Major Blood Vessel of the Heart]; NCT00092677).

Prognostic effect of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis

Objectives In patients with aortic stenosis (AS) left ventricular (LV) myocardial growth may exceed individual needs to compensate LV haemodynamic load leading to inappropriately high LV mass (iLVM), a condition at high risk of adverse cardiovascular events. The prognostic impact of iLVM was determined in 218 patients with asymptomatic severe AS. Methods iLVM was recognised when the measured LV mass exceeded 10% of the expected value predicted from height, sex and stroke work (prognostic cut-off assessed by a specific ROC analysis). For assessment of outcome, the endpoint was defined as death from all causes, aortic valve replacement or hospital admission for non-fatal myocardial infarction and/or congestive heart failure. Results At the end of follow-up (22+13 months) complete clinical data were available for 209 participants (mean age 75+11 years). A clinical event occurred in 81 of 121 patients (67%) with iLVM and in 26 of 88 patients (30%) with appropriate LV mass (aLVM) (p<0.001). Event-free survival in patients with aLVM and iLVM was 78% vs 56% at 1-year, 68% vs 29% at 3-year and 56% vs 10% at 5-year follow-up, respectively (all p<0.01). Cox analysis identified iLVM as a strong predictor of adverse outcome (Exp β 3.08; CI 1.65 to 5.73) independent of diabetes, transaortic valve peak gradient and extent of valvular calcification. Among patients with LV hypertrophy, those with iLVM had a risk of adverse events 4.5-fold higher than counterparts with aLVM. Conclusions iLVM is common in patients with asymptomatic severe AS and is associated with an increased rate of cardiovascular events independent of other prognostic covariates.

Impact of left ventricular geometry on prognosis in hypertensive patients with left ventricular hypertrophy (the LIFE study)

AIMS Less is known about the relation between in-treatment left ventricular (LV) geometry and risk of cardiovascular events. We assessed LV geometric patterns on baseline and annual echocardiograms as time-varying predictors of the primary composite endpoint (cardiovascular death, stroke, and myocardial infarction) in 937 hypertensive patients with LV hypertrophy during 4.8 years losartan- or atenolol-based treatment in the Losartan Intervention for Endpoint reduction in hypertension (LIFE) echocardiography substudy. METHODS AND RESULTS LV geometry was determined from LV mass/body surface area and relative wall thickness in combination. At end of the study, 52% of patients with initial LV hypertrophy had normal geometry (P < 0.001). In particular, concentric remodelling was reduced by 82% and concentric LV hypertrophy by 84%. Development of LV hypertrophy was seen in <5%. In Cox regression analyses including LV geometric patterns as time-varying variables and adjusting for treatment, Framingham risk score, race, and time-varying systolic blood pressure, the patterns independently predicted higher risk of primary composite endpoints [HR 2.99 (1.16-7.71) for concentric remodelling, HR 1.79 (1.17-2.73) for eccentric hypertrophy, and HR 2.71 (1.13-6.45) for concentric hypertrophy; all P < 0.05]. CONCLUSION In hypertensive patients with ECG LV hypertrophy, in-treatment LV geometry by echocardiography adds information on risk of cardiovascular events.

Myocardial deformation in aortic valve stenosis: relation to left ventricular geometry.

Objective To assess left ventricular (LV) strain and displacement and their relations to LV geometry in patients with aortic stenosis (AS). Design Cross-sectional echocardiographic study in patients with AS. Peak circumferential, radial and longitudinal strain, and radial, longitudinal and transverse displacement were measured by 2D speckle tracking. Severity of AS was assessed from energy loss index (ELI). LV hypertrophy was present if LV mass/height2.7 ≥46.7/49.2 g/m2.7 in women/men and concentric LV geometry if relative wall thickness ≥0.43. LV geometry was assessed from LV mass/height2.7 and relative wall thickness in combination. Setting Department of Heart Disease, Haukeland University Hospital, Bergen, Norway. Patients 70 patients with AS (mean age 73±10 years, 54% women). Interventions None. Main outcome measures Association of regional and average LV myocardial strain and displacement with LV geometric pattern and degree of AS. Results Average longitudinal strain was lower in the hypertrophy groups and correlated with higher LV mass index and relative wall thickness, lower stress-corrected mid-wall shortening and smaller ELI (all p<0.05). Average strain and displacement in other directions did not differ between geometric groups. In multivariate regression analysis, lower average longitudinal strain was associated with higher relative wall thickness (β=0.15), lower ejection fraction (β=−0.16), systolic blood pressure (β=−0.16) and energy loss index (β=−0.20) (all p<0.05) (R2=0.72). When relative wall thickness was replaced with LV mass, lower longitudinal strain was also associated with higher LV mass (β=0.21, p<0.05) (R2=0.73). Conclusions In patients with AS, lower average longitudinal strain is related to higher LV mass, concentric geometry and more severe AS.

Impact of Pressure Recovery on Echocardiographic Assessment of Asymptomatic Aortic Stenosis: A SEAS Substudy

OBJECTIVES The aim of this analysis was to assess the diagnostic importance of pressure recovery in evaluation of aortic stenosis (AS) severity. BACKGROUND Although pressure recovery has previously been demonstrated to be particularly important in assessment of AS severity in groups of patients with moderate AS or small aortic roots, it has never been evaluated in a large clinical patient cohort. METHODS Data from 1,563 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was used. Inner aortic diameter was measured at annulus, sinus, sinotubular junction, and supracoronary level. Aortic valve area index (AVAI) was calculated by continuity equation and pressure recovery and pressure recovery adjusted AVAI (energy loss index [ELI]), by validated equations. Primarily, sinotubular junction diameter was used to calculate pressure recovery and ELI, but pressure recovery and ELI calculated at different aortic root levels were compared. Severe AS was identified as AVAI and ELI < or =0.6 cm(2)/m(2). Patients were grouped into tertiles of peak transaortic velocity. RESULTS Pressure recovery increased with increasing peak transaortic velocity. Overestimation of AS severity by unadjusted AVAI was largest in the lowest tertile and if pressure recovery was assessed at the sinotubular junction. In multivariate analysis, a larger difference between AVAI and ELI was associated with lower peak transaortic velocity (beta = 0.35) independent of higher left ventricular ejection fraction (beta = -0.049), male sex (beta = -0.075), younger age (beta = 0.093), and smaller aortic sinus diameter (beta = 0.233) (multiple R(2) = 0.18, p < 0.001). Overall, 47.5% of patients classified as having severe AS by AVAI were reclassified to nonsevere AS when pressure recovery was taken into account. CONCLUSIONS For accurate assessment of AS severity, pressure recovery adjustment of AVA must be routinely performed. Estimation of pressure recovery at the sinotubular junction is suggested.

Prognostic Value of Energy Loss Index in Asymptomatic Aortic Stenosis

Background— Aortic valve area index adjusted for pressure recovery (energy loss index [ELI]) has been suggested as a more accurate measure of aortic stenosis (AS) severity, but its prognostic value has not been determined in a prospective study. Methods and Results— The relation between baseline ELI and rate of aortic valve events and combined total mortality and hospitalization for heart failure resulting from the progression of AS was assessed by multivariate Cox regression and reclassification analysis in 1563 patients with initial asymptomatic AS in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. During 4.3 years follow-up, a total of 498 aortic valve events and 181 combined total mortalities and hospitalizations for heart failure caused by the progression of AS occurred. In Cox regression analyses, 1-cm2/m2 lower baseline ELI predicted a 2-fold higher risk both for aortic valve events and for combined total mortality and hospitalization for heart failure independently of baseline peak aortic jet velocity or mean aortic gradient and independently of aortic root size (all P<0.05). In reclassification analysis, ELI improved the prediction of aortic valve events by 13% (95% confidence interval, 5–19), whereas the prediction of combined total mortality and hospitalization for heart failure resulting from the progression of AS did not improve significantly. Conclusions— In asymptomatic AS patients without known atherosclerotic disease or diabetes mellitus, ELI provides independent and additional prognostic information to that derived from conventional measures of AS severity, suggesting that ELI should be measured in such patients. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Gender Differences in Left Ventricular Structure and Function During Antihypertensive Treatment The Losartan Intervention for Endpoint Reduction in Hypertension Study

In hypertensive patients with left ventricular hypertrophy, antihypertensive treatment induces changes in left ventricular structure and function. However, less is known about gender differences in this response. Baseline and annual echocardiograms until the end of study or a primary end point occurred were assessed in 863 hypertensive patients with electrocardiographic left ventricular hypertrophy aged 55 to 80 years (mean: 66 years) during 4.8 years of randomized losartan- or atenolol-based treatment in the Losartan Intervention for Endpoint Reduction in Hypertension Echocardiography substudy. Left ventricular hypertrophy was diagnosed as left ventricular mass divided by height2.7 ≥46.7 g/m2.7 and 49.2 g/m2.7 in women and men, respectively, and systolic function as ejection fraction and stress-corrected midwall fractional shortening. Women included more patients with obesity, isolated systolic hypertension, and mitral regurgitation (all P<0.01). Ejection fraction, stress-corrected midwall shortening, and prevalence of left ventricular hypertrophy were higher in women at baseline and at the end of study (all P<0.01). In particular, more women had residual eccentric hypertrophy (47% versus 32%; P<0.01) in spite of similar in-treatment reduction in mean blood pressure. In logistic regression, left ventricular hypertrophy at study end was more common in women (odds ratio: 1.61; 95% CI: 1.16 to 2.26; P<0.01) independent of other significant covariates. In linear regression analyses, female gender also predicted 2% higher mean in-treatment ejection fraction and 2% higher mean stress-corrected midwall shortening (both &bgr;=0.07; P<0.01). Hypertensive women in this study retained higher left ventricular ejection fraction and stress-corrected midwall shortening in spite of less hypertrophy regression during long-term antihypertensive treatment.

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}

Original ResearchImpact of Pressure Recovery on Echocardiographic Assessment of Asymptomatic Aortic Stenosis: A SEAS Substudy

OBJECTIVES The aim of this analysis was to assess the diagnostic importance of pressure recovery in evaluation of aortic stenosis (AS) severity. BACKGROUND Although pressure recovery has previously been demonstrated to be particularly important in assessment of AS severity in groups of patients with moderate AS or small aortic roots, it has never been evaluated in a large clinical patient cohort. METHODS Data from 1,563 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was used. Inner aortic diameter was measured at annulus, sinus, sinotubular junction, and supracoronary level. Aortic valve area index (AVAI) was calculated by continuity equation and pressure recovery and pressure recovery adjusted AVAI (energy loss index [ELI]), by validated equations. Primarily, sinotubular junction diameter was used to calculate pressure recovery and ELI, but pressure recovery and ELI calculated at different aortic root levels were compared. Severe AS was identified as AVAI and ELI < or =0.6 cm(2)/m(2). Patients were grouped into tertiles of peak transaortic velocity. RESULTS Pressure recovery increased with increasing peak transaortic velocity. Overestimation of AS severity by unadjusted AVAI was largest in the lowest tertile and if pressure recovery was assessed at the sinotubular junction. In multivariate analysis, a larger difference between AVAI and ELI was associated with lower peak transaortic velocity (beta = 0.35) independent of higher left ventricular ejection fraction (beta = -0.049), male sex (beta = -0.075), younger age (beta = 0.093), and smaller aortic sinus diameter (beta = 0.233) (multiple R(2) = 0.18, p < 0.001). Overall, 47.5% of patients classified as having severe AS by AVAI were reclassified to nonsevere AS when pressure recovery was taken into account. CONCLUSIONS For accurate assessment of AS severity, pressure recovery adjustment of AVA must be routinely performed. Estimation of pressure recovery at the sinotubular junction is suggested.