Impact of aortic valve stenosis on myocardial deformation in different left ventricular levels: A three-dimensional speckle tracking echocardiography study.

BACKGROUND: Global systolic left ventricular (LV) myocardial function progressively declines as degenerative aortic valve stenosis (AS) progresses. Whether this results in uniformly distributed deformation changes from base to apex has not been investigated. METHODS: Eighty-five AS patients underwent three-dimensional (3D) echocardiography in this cross-sectional study. Patients were grouped by peak jet velocity into mild (n = 32), moderate (n = 31), and severe (n = 22) AS. 3D speckle tracking derived strain, rotation, twist, and torsion were obtained to assess global LV function and myocardial function at the apical, mid, and basal levels. RESULTS: Global longitudinal strain (GLS) was lower in patients with severe AS (-16.1 ± 2.4% in mild, -15.5 ± 2.5% in moderate, and -13.5 ± 3.0% in severe AS [all p < .01]). Peak basal and mid longitudinal strain (LS), basal rotation and twist from apical to basal level followed the same pattern, while peak apical LS was higher in moderate AS compared to severe AS (all p < .05). In multivariate analyses, lower GLS was particularly associated with male sex, higher body mass index and peak aortic jet velocity, lower basal LS with higher filling pressure (E/e') and LV mass, lower mid LS with higher RWT and presence of AS symptoms, and lower apical LS with male sex and higher systolic blood pressure, respectively (all p < .05). CONCLUSION: Using 3D speckle tracking echocardiography reveals regional and global changes in LV mechanics in AS related to the severity of AS, LV remodeling and presence of cardiovascular risk factors.

Myocardial Work in Middle-Aged Adults with Overweight and Obesity: Associations with Sex and Central Arterial Stiffness.

We explored global myocardial work index (GWI), a novel measure of myocardial function that integrates left ventricular (LV) hemodynamic load, in relation to sex and increased body mass index (BMI). We used data from 467 individuals (61% women, average age 47 ± 9 years and BMI 31.2 kg/m2) without known cardiac disease. Central arterial function was analysed by applanation tonometry. GWI was calculated from global longitudinal strain (GLS) and post-echocardiography supine blood pressure (BP). Covariables of GWI were identified in linear regression analyses. Women had higher BMI, aortic augmentation pressure (12 ± 7 vs. 8 ± 6 mmHg), LV GLS (20.0 ± 2.8 vs. 18.8 ± 2.8%), and GWI (2126 ± 385 vs. 2047 ± 389 mmHg%) than men (all p < 0.05). In univariable analyses, higher GWI was associated with female sex, higher age, systolic BP, LV wall stress, LV ejection fraction, left atrial size, LV ejection time, and with lower waist circumference (all p < 0.05). In multivariable analysis, adjusting for these correlates, female sex remained independently associated with higher GWI (ß = 0.13, p = 0.007). After additional adjustment for aortic augmentation pressure or central pulse pressure, this association became non-significant. In conclusion, the higher GWI in women compared to men was mainly explained by increased LV workload due to higher aortic augmentation pressure in women.

Prognosis in asymptomatic patients with discordantly graded aortic valve stenosis based on pressure recovery adjusted valve area.

OBJECTIVE: We hypothesised that patients with asymptomatic aortic stenosis (AS) who remain with discordantly graded aortic valve stenosis (DGAS) after adjustment for pressure recovery in the aortic root represents a subgroup of patients with increased cardiovascular risk. METHODS: Data from 1353 patients with asymptomatic mild-moderate AS and preserved left ventricular ejection fraction enrolled in the Simvastatin and Ezetimibe in AS study was used. DGAS was identified as combined pressure adjusted valve area (energy loss) <1.0 cm² and mean aortic gradient<40 mm Hg (DGASEL). Outcome was assessed in Cox regression analysis and reported as HR and 95% CI. RESULTS: DGASEL was found in 196 (14.5%) patients at baseline, and was associated with older age, female sex, smaller aortic annulus diameter, lower heart rate, more extensive valve calcification and low flow (all p<0.05). In Cox regression analysis, DGASEL was associated with higher rate of heart failure (HF) hospitalisation (HR 3.31 (95% CI 1.54 to 7.09)), cardiovascular death (HR 2.63 (95% CI 1.34 to 5.17)) and all-cause mortality (HR 1.73 (95% CI 1.04 to 2.87)) independent of confounders including low flow and aortic valve calcification (all p<0.05). CONCLUSIONS: Patients with asymptomatic AS who remain with discordant grading after adjustment for pressure recovery have increased risk for HF and death. TRIAL REGISTRATION NUMBER: NCT00092677.

Higher Acceleration/Ejection Time Ratio Predicts Impaired Outcome in Aortic Valve Stenosis.

BACKGROUND: Acceleration time (AT)/ejection time (ET) ratio is a marker of aortic valve stenosis (AS) severity and predicts outcome in moderate-severe AS. METHODS: We explored the association of increased AT/ET ratio on prognosis in 1530 asymptomatic patients with presumably mild-moderate AS, normal ejection fraction, and without known diabetes or cardiovascular disease. Patients were part of the SEAS study (Simvastatin Ezetimibe Aortic Stenosis). Patients were grouped according to the optimal AT/ET ratio threshold to predict cardiovascular death and heart failure hospitalization. Low-gradient severe AS was identified as combined valve area ≤1.0 cm2 and mean gradient <40 mm Hg. Outcome was assessed in Cox regression analyses, and results are reported as hazard ratio and 95% CI. RESULTS: Higher AT/ET ratio was significantly associated with lower systolic blood pressure, lower left ventricular ejection fraction, lower stress-corrected midwall shortening, low flow, and with higher left ventricular mass and higher peak aortic jet velocity. AT/ET ratio ≥0.32 provided the optimal cutoff for predicting incident cardiovascular death and heart failure hospitalization in the total study sample. In patients with low-gradient severe AS, this threshold was >0.32. AT/ET ratio ≥0.32 had a 79% higher risk of cardiovascular death and heart failure hospitalization (hazard ratio, 1.79 [95% CI, 1.20-2.68]). In patients with low-gradient severe AS, AT/ET ratio >0.32 was associated with a 2-fold higher risk of cardiovascular death and heart failure hospitalization (hazard ratio, 2.15 [95% CI, 1.22-3.77]). CONCLUSIONS: In asymptomatic nonsevere AS and low-gradient severe AS, higher AT/ET ratio was associated with increased cardiovascular morbidity and mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00092677.

Low myocardial energetic efficiency is associated with increased mortality in aortic stenosis.

OBJECTIVES: In hypertension, low myocardial energetic efficiency (MEEi) has been documented as an integrated marker of metabolic and left ventricular (LV) myocardial dysfunction. We tested the predictive performance of MEEi in initially asymptomatic aortic stenosis (AS) patients free from diabetes and known cardiovascular disease. METHODS: Data from 1703 patients with mostly moderate AS enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study followed for 4.3 years was used. MEE was calculated from Doppler stroke volume/([heart rate/60]) and indexed to LV mass (MEEi). The threshold value for MEEi associated with increased mortality was identified in generalised additive model with smoothing splines. Covariables of MEEi were identified in logistic regression analysis. Outcome was assessed in Cox regression analysis and reported as HR and 95% CI. RESULTS: MEEi <0.34 mL/s per gram was associated with increased cardiovascular mortality (n=80) (HR 2.53 (95% CI 1.50 to 4.28)) and all-cause mortality (n=155) (HR 1.74 (95% CI 1.20 to 2.52)) (both p<0.01). The association was independent of confounders of low MEEI (<0.34 mL/s per gram) identified in multivariable logistic regression analysis, including more severe AS, higher body mass index, lower LV midwall shortening and ejection fraction and presence of hypertension. Comparison of the Cox models with and without MEEi among the covariables demonstrated that MEEi significantly improved the prognostic yield (both p<0.01). CONCLUSIONS: In patients with initially asymptomatic AS, low MEEi was associated with clustering of cardiometabolic risk factors, lower LV myocardial function and subsequent increased mortality during 4.3 years follow-up, independent of known prognosticators. TRIAL REGISTRATION NUMBER: NCT00092677.

Impact of arterio-ventricular interaction on first-phase ejection fraction in aortic stenosis.

AIMS: First-phase ejection fraction (EF1), the EF at the time to peak aortic jet velocity, has been proposed as a novel marker of peak systolic function in aortic stenosis (AS). This study aimed to explore the association of myocardial contractility and arterial load with EF1 in AS patients. METHODS AND RESULTS: Data from a prospective, cross-sectional study of 114 patients with mild, moderate, and severe AS with preserved left ventricular EF (>50%) were analysed. EF1 was measured as the volume change from end-diastole to the time that corresponded to peak aortic jet velocity. Myocardial contractility was assessed by strain rate measured by speckle tracking echocardiography. Arterial stiffness was assessed by central pulse pressure/stroke volume index ratio (PP/SVi). The total study population included 48% women, median age was 73 years, and mean peak aortic jet velocity was 3.47 m/s. In univariable linear regression analyses, lower EF1 was associated with higher age, higher peak aortic jet velocity, lower global EF, lower global longitudinal strain, lower strain rate, and higher PP/SVi. There was no significant association between EF1 and heart rate or sex. In multivariable linear regression analysis, EF1 was associated with lower strain rate and higher PP/SVi, independent of AS severity. Replacing PP/SVi by valvular impedance did not change the results. CONCLUSION: In patients with AS, reduced myocardial contractility and increased arterial load were associated with lower EF1 independent of the severity of valve stenosis.

First-Phase Ejection Fraction Predicts Response to Cardiac Resynchronization Therapy and Adverse Outcomes.

OBJECTIVES: The aim of this study was to examine the value of first-phase ejection fraction (EF1), to predict response to cardiac resynchronization therapy (CRT) and clinical outcomes after CRT. BACKGROUND: CRT is an important treatment for patients with chronic heart failure. However, even in carefully selected cases, up to 40% of patients fail to respond. EF1, the ejection fraction up to the time of maximal ventricular contraction, is a novel sensitive echocardiographic measure of early systolic function and might relate to response to CRT. METHODS: An initial retrospective study was performed in 197 patients who underwent CRT between 2009 and 2018 and were followed to determine clinical outcomes at King's Health Partners in London. A validation study (n = 100) was performed in patients undergoing CRT at Barts Heart Centre in London. RESULTS: Volumetric response rate (reduction in end-systolic volume ≥15%) was 92.3% and 12.1% for those with EF1 in the highest and lowest tertiles (P < 0.001). A cutoff value of 11.9% for EF1 had >85% sensitivity and specificity for prediction of response to CRT; on multivariate binary logistic regression analysis incorporating previously defined predictors, EF1 was the strongest predictor of response (odds ratio [OR]: 1.56 per 1% change in EF1; 95% CI: 1.37-1.78; P < 0.001). EF1 was also the strongest predictor of improvement in clinical composite score (OR: 1.11; 95% CI: 1.04-1.19; P = 0.001). Improvement in EF1 at 6 months after CRT implantation (6.5% ± 5.8% vs 1.8% ± 4.3% in responders vs nonresponders; P < 0.001) was the best predictor of heart failure rehospitalization and death after median follow-up period of 20.3 months (HR: 0.81; 95% CI: 0.73-0.90; P < 0.001). In the validation cohort, EF1 was a similarly 1strong predictor of response (OR: 1.45; 95% CI: 1.23-1.70; P < 0.001) as in the original cohort. CONCLUSIONS: EF1 is a promising marker to identify patients likely to respond to CRT.

Association of increased arterial stiffness with diastolic dysfunction in ischemic stroke patients: the Norwegian Stroke in the Young Study.

BACKGROUND: Young and middle-aged ischemic stroke survivors have a high prevalence of hypertension, increased arterial stiffness and abnormal left ventricular (LV) geometry, which all are associated with the presence of LV diastolic dysfunction. However, the prevalence and covariates of diastolic dysfunction in these patients have not been reported. OBJECTIVES: To explore diastolic dysfunction in ischemic stroke patients aged 15-60 years included in the Norwegian Stroke in the Young Study. METHODS: Data from 260 patients with acute ischemic stroke was analyzed. Diastolic dysfunction was assessed by combining transmitral peak early flow (E), early diastolic mitral annular velocity (e'), E/e' ratio, left atrial volume index and peak tricuspid regurgitant jet velocity, following current European guidelines. Carotid-femoral pulse wave velocity at least 10 m/s by aplanation tonometry was defined as increased arterial stiffness. RESULTS: Prevalent diastolic dysfunction was found in 20% of patients (13% with diastolic dysfunction grade 1 and 7% with diastolic dysfunction grades 2-3). Patients with diastolic dysfunction were older and more likely to have hypertension, overweight, increased arterial stiffness, higher LV mass and less percentage nightly reduction in mean blood pressure (BP) (all P < 0.001). In a multivariable logistic regression analysis, diastolic dysfunction was associated with increased arterial stiffness [odds ratio 2.86 (95% confidence interval 1.05-7.79), P < 0.05] independent of age more than 45 years, overweight, hypertension, night-time BP reduction and LV mass. CONCLUSION: Among young and middle-aged ischemic stroke survivors, diastolic dysfunction was found in 20%. The presence of diastolic dysfunction was associated with increased arterial stiffness independent of higher age, overweight, hypertension, night-time BP reduction and LV mass.

Impact of Obesity on Persistent Left Ventricular Hypertrophy After Aortic Valve Replacement for Aortic Stenosis.

Normalization of left ventricular (LV) hypertrophy is expected after successful aortic valve replacement (AVR) in patients with aortic valve stenosis (AS), but is not always observed. We tested the impact of body mass index (BMI) ≥30 kg/m2 on persistent post-AVR LV hypertrophy. In the present subanalysis of Simvastatin Ezetimibe in Aortic Stenosis study, clinical and echocardiographic data of 399 patients with severe AS who underwent surgical AVR were analyzed. All patients had a standardized pre- and post-AVR echocardiogram. Patients were grouped by BMI categories into BMI <25 kg/m2, BMI 25 to 29.9 kg/m2, and BMI ≥30 kg/m2. LV hypertrophy was defined as LV mass/height2.7 >49.2 g/m2.7 in men and >46.7 g/m2.7 in women. Predictors of persistent LV hypertrophy after AVR were identified in logistic regression analysis. After a median follow-up of 196 days after AVR, LV hypertrophy was more prevalent in patients with BMI ≥30 kg/m2 compared with those with BMI 25 to 29.9 kg/m2 and those patients with BMI <25 kg/m2 (71% vs 47% and 37%, p <0.01). BMI ≥30 kg/m2 patients also remained with lower LV midwall shortening post-AVR compared with patients with normal weight (p <0.01), independent of patient prosthesis mismatch. In multivariable logistic regression analysis, the presence of BMI ≥30 kg/m2 before AVR was associated with an almost fourfold higher prevalence of post-AVR LV hypertrophy independent of significant associations with higher systolic blood pressure and lower LV midwall shortening preoperatively (odds ratio 3.75 [95% confidence interval 2.04 to 6.91], p <0.001). In conclusion, the presence of BMI ≥30 kg/m2 before AVR in patients with severe AS was strongly and independently associated with persistent post-AVR LV hypertrophy.

Higher left ventricular mass-wall stress-heart rate product and outcome in aortic valve stenosis.

OBJECTIVE: Whether increased myocardial oxygen demand could help explain the association of left ventricular (LV) hypertrophy with higher adverse event rate in patients with aortic valve stenosis (AS) is unknown. METHODS: Data from 1522 patients with asymptomatic mostly moderate AS participating in the Simvastatin-Ezetimibe in AS study followed for a median of 4.3 years was used. High LV mass-wall stress-heart rate product was identified as >upper 95% CI limit in normal subjects. The association of higher LV mass-wall stress-heart rate product with major cardiovascular (CV) events, combined CV death and hospitalised heart failure and all-cause mortality was tested in Cox regression analyses, and reported as HR and 95% CI. RESULTS: High LV mass-wall stress-heart rate product was found in 19% at baseline, and associated with male sex, higher body mass index, hypertension, LV hypertrophy, more severe AS and lower LV ejection fraction (all p<0.01). Adjusting for these confounders in time-varying Cox regression analysis, 1 SD higher LV mass-wall stress-heart rate product was associated with higher HR of major CV events (HR 1.16(95% CI 1.06 to 1.29)), combined CV death and hospitalised heart failure (HR 1.29(95% CI 1.09 to 1.54)) and all-cause mortality (HR 1.34(95% CI 1.13 to 1.58), all p<0.01). CONCLUSION: In patients with initially mild-moderate AS, higher LV mass-wall stress-heart rate product was associated with higher mortality and heart failure hospitalisation. Our results suggest that higher myocardial oxygen demand is contributing to the higher adverse event rate reported in AS patients with LV hypertrophy. TRIAL REGISTRATION NUMBER: NCT000092677;Post-results.

Echocardiographic aortic valve calcification and outcomes in women and men with aortic stenosis.

OBJECTIVE: Sex differences in risk factors of aortic valve calcification (AVC) by echocardiography have not been reported from a large prospective study in aortic stenosis (AS). METHODS: AVC was assessed using a prognostically validated visual score and grouped into none/mild or moderate/severe AVC in 1725 men and women with asymptomatic AS in the Simvastatin Ezetimibe in Aortic Stenosis study. The severity of AS was assessed by the energy loss index (ELI) taking pressure recovery in the aortic root into account. RESULTS: More men than women had moderate/severe AVC at baseline despite less severe AS by ELI (p<0.01). Moderate/severe AVC at baseline was independently associated with lower aortic compliance and more severe AS in both sexes, and with increased high-sensitive C reactive protein (hs-CRP) only in men (all p<0.01). In Cox regression analyses, moderate/severe AVC at baseline was associated with a 2.5-fold (95% CI 1.64 to 3.80) higher hazard rate of major cardiovascular events in women, and a 2.2-fold higher hazard rate in men (95% CI 1.54 to 3.17) (both p<0.001), after adjustment for age, hypertension, study treatment, aortic compliance, left ventricular (LV) mass and systolic function, AS severity and hs-CRP. Moderate/severe AVC at baseline also predicted a 1.8-fold higher hazard rate of all-cause mortality in men (95% CI 1.04 to 3.06, p<0.05) independent of age, AS severity, LV mass and aortic compliance, but not in women. CONCLUSION: In conclusion, AVC scored by echocardiography has sex-specific characteristics in AS. Moderate/severe AVC is associated with higher cardiovascular morbidity in both sexes, and with higher all-cause mortality in men. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT00092677.

Comparison of Frequency of Ischemic Cardiovascular Events in Patients With Aortic Stenosis With Versus Without Asymmetric Septal Hypertrophy (from the SEAS Trial).

Asymmetric interventricular septum hypertrophy (ASH) has been associated with increased perioperative morbidity and mortality in patients with severe, symptomatic aortic valve stenosis (AS). Less is known about the prognostic impact of ASH during progression of AS. Clinical, echocardiographic, and outcome data from 1,691 patients with initially asymptomatic, mostly moderate AS, participating in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study was used. ASH was considered present if interventricular septum/posterior wall thickness ratio in end-diastole ≥1.5. The associations of ASH with hazard rate of ischemic cardiovascular events were tested in time-dependent Cox regression analyses. Based on the presence of ASH at study echocardiograms, the study population was grouped in to a no-ASH, nonpersistent ASH, persistent ASH, and new-onset ASH groups. During a median of 4.3 years of follow-up, ASH persisted or developed in 17% of patients. Persistent or new-onset ASH was characterized by higher left ventricular mass index and ejection fraction at baseline (both p <0.05) but not with female gender or hypertension. In time-varying Cox regression analyses adjusting for these confounders, persistent or new-onset ASH was associated with higher hazard rate of ischemic cardiovascular events (hazard rate 1.45; 95% confidence interval 1.09 to 1.91, p = 0.01), in particular coronary artery bypass grafting (hazard rate 1.69; 95% confidence interval 1.17 to 2.47; p = 0.006), whereas no association with increased mortality was found. In conclusion, in patients with AS without diabetes or known renal or cardiovascular disease participating in the SEAS study, persistent or new-onset ASH during progression of AS was associated with higher rate of ischemic cardiovascular events.