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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}

Relation of Left Ventricular Mass to Prognosis in Initially Asymptomatic Mild to Moderate Aortic Valve Stenosis

Background—The prognostic importance of left ventricular (LV) mass in nonsevere asymptomatic aortic stenosis has not been documented in a large prospective study. Methods and Results—Cox regression analysis was used to assess the impact of echocardiographic LV mass on rate of major cardiovascular events in 1656 patients (mean age, 67 years; 39.6% women) with mild-to-moderate asymptomatic aortic stenosis participating in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. Patients were followed during 4.3 years of randomized treatment with combined simvastatin 40 mg and ezetimibe 10 mg daily or placebo. At baseline, LV mass index was 45.9+14.9 g/m2.7, and peak aortic jet velocity was 3.09+0.54 m/s. During follow-up, 558 major cardiovascular events occurred. In Cox regression analyses, 1 SD (15 g/m2.7) higher baseline LV mass index predicted increases in hazards of 12% for major cardiovascular events, 28% for ischemic cardiovascular events, 34% for cardiovascular mortality, and 23% for combined total mortality and hospitalization for heart failure (all P<0.01), independent of confounders. In time-varying models, taking the progressive increase in LV mass index during follow-up into account, 1 SD higher in-study LV mass index was consistently associated with 13% to 61% higher hazard for cardiovascular events (all P<0.01), independent of age, sex, body mass index, valvuloarterial impedance, LV ejection fraction and concentricity, and the presence of concomitant hypertension. Conclusions—Higher LV mass index is independently associated with increased cardiovascular morbidity and mortality during progression of aortic stenosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Sex differences in cardiovascular outcome during progression of aortic valve stenosis

Objective Women with severe aortic valve stenosis (AS) have better LV systolic function and more concentric LV geometry than their male counterparts. However, sex differences in cardiovascular (CV) outcome during progression of AS have not been reported from a longitudinal prospective study. Methods Doppler echocardiography and CV events were recorded during a median of 4.0 years in 979 men and 632 women aged 28–86 (mean 67±10) years in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. LV systolic function was assessed by EF and midwall shortening (MWS). Study outcomes were AS-related events, ischaemic CV events and total mortality. Results The annular cumulative incidence of AS events, ischaemic CV events and death was 8.1%, 3.4% and 2.8% in women, and 8.9%, 4.4% and 2.4% in men, respectively. Women and men had similar AS progression rate whether measured by peak jet velocity, mean gradient or valve area. In multivariate analyses, female sex independently predicted less reduction in LV MWS and EF during follow-up (both p<0.05). In time-varying Cox analyses, women had a 40% lower rate of ischaemic CV events (95% CI 21% to 54%), in particular, more than 50% lower rate of stroke and coronary artery bypass grafting, and a 31% lower all-cause mortality (95% CI 1% to 51%), independent of active study treatment, age and hypertension, as well as time-varying valve area, low systolic function and abnormal LV geometry. AS event rate did not differ by sex. Conclusions In the SEAS study, women and men had similar rates of AS progression and AS-related events. However, women had lower total mortality and ischaemic CV event rate than men independent of confounders. Trial registration number ClinicalTrials.gov identifier: NCT00092677.

Left Ventricular Hypertrophy Regression During Antihypertensive Treatment in an Outpatient Clinic (the Campania Salute Network)

Background Regression of left ventricular (LV) hypertrophy (LVH) has been a goal in clinical trials. This study tests the external validity of results of clinical trials on LVH regression using a large registry from a tertiary care center, to identify phenotypes less likely to achieve regression of LVH. Methods and Results Patients from the Campania Salute Network, free of prevalent cardiovascular disease, but with echocardiographic LVH (defined as LV mass index [LVMi] >47 g/m2.7 in women and >50 g/m2.7 in men) were included. During a median follow‐up of 67 months, clear‐cut regression of LVH was documented in 14% of patients (13±8% reduction of initial LVMi) or 23% when also considering those with a reduction of LVMi ≥5 g/m2.7. Patients with persistent LVH were older with longer duration of hypertension, suboptimal blood pressure (BP) control, larger body mass index, LV mass, and carotid intima‐media thickness and included more women and subjects with diabetes mellitus, isolated systolic hypertension, and metabolic syndrome (all P<0.05). Number and class of antihypertensive drugs during follow‐up did not differ between groups. In multiple logistic regression analysis, older age, female sex, obesity, higher baseline LVMi and carotid intima‐media thickness, and suboptimal BP control were significant covariates of persistent LVH (all P≤0.01), independent of diabetes, duration of hypertension, isolated systolic hypertension, follow‐up time and number and class of antihypertensive drugs. Conclusions Early initiation of antihypertensive treatment, aggressive BP control, and attention to metabolic aspects are critical to avoid irreversible LVH.

Impact of isolated systolic hypertension on normalization of left ventricular structure during antihypertensive treatment (the LIFE study)

Abstract Objective. We tested the impact of isolated systolic hypertension (ISH) on normalization of left ventricular (LV) structure during antihypertensive treatment. Methods. Baseline and annual echocardiograms were recorded in 873 hypertensive patients with electrocardiographic signs of LV hypertrophy during 4.8 years randomized losartan- or atenolol-based antihypertensive treatment in the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study and classified as having ISH (n = 128) if systolic BP ≥ 160 mmHg and diastolic BP < 90 mmHg, or non-ISH divided into two groups by systolic BP ≥ 160 mmHg (non-ISH ≥ 160 mmHg) (n = 645) and systolic BP < 160 mm Hg (n = 100) (non-ISH < 160 mmHg), respectively. Results. Patients with ISH were older, with higher prevalence of diabetes than non-ISH groups and higher pulse pressure/stroke volume index (all p < 0.05). Baseline systolic blood pressure (BP) differed between groups and was highest in the non-ISH ≥ 160 mmHg group (p < 0.05). Systolic BP reduction was less in the ISH group (p < 0.05). LV geometry did not differ between ISH and non-ISH ≥ 160 mmHg groups at baseline, but ISH had more residual LV hypertrophy of concentric type at the last study visit (p < 0.05). In multivariate analysis, less reduction of LV mass was predicted by ISH (β = − 0.07) independent of significant associations with baseline LVMi (β = 0.52) and atenolol-based treatment (β = − 0.08) and clinical confounders (all p < 0.05). Conclusions. ISH is associated with impaired normalization of LV mass during systematic antihypertensive treatment. The findings may help explain the higher cardiovascular event rate previously reported in ISH patients.

Global left ventricular load in asymptomatic aortic stenosis: covariates and prognostic implication (the SEAS trial)

IntroductionValvuloarterial impedance (Zva) is a measure of global (combined valvular and arterial) load opposing left ventricular (LV) ejection in aortic stenosis (AS). The present study identified covariates and tested the prognostic significance of global LV load in patients with asymptomatic AS.Methods1418 patients with mild-moderate, asymptomatic AS in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study were followed for a mean of 43±14 months during randomized, placebo-controlled treatment with combined simvastatin 40 mg and ezetimibe 10 mg daily. High global LV load was defined as Zva >5 mm Hg/ml/m2. The impact of baseline global LV load on rate of major cardiovascular (CV) events, aortic valve events and total mortality was assessed in Cox regression models reporting hazard ratio (HR) and 95% Confidence Intervals (CI).ResultsHigh global LV load was found in 18% (n=252) of patients and associated with female gender, higher age, hypertension, more severe AS and lower ejection fraction (all p<0.05). A total of 476 major CV events, 444 aortic valve events and 132 deaths occurred during follow-up. In multivariate Cox regression analyses, high global LV load predicted higher rate of major CV events (HR 1.35 [95% CI 1.08-1.71], P=0.010) and aortic valve events (HR 1.41 [95% CI 1.12-1.79], P=0.004) independent of hypertension, LV ejection fraction, female gender, age, abnormal LV geometry and AS severity, but failed to predict mortality.ConclusionIn asymptomatic AS, assessment of global LV load adds complementary information on prognosis to that provided by hypertension or established prognosticators like AS severity and LV ejection fraction.

Usefulness of Contrast Echocardiography for Predicting the Severity of Angiographic Coronary Disease in Non-ST-Elevation Myocardial Infarction

Guidelines recommend coronary angiography in patients with non-ST-elevation myocardial infarction (NSTEMI) within 24 to 72 hours, a requirement that cannot always be met. The aim of this study was to evaluate the potential use of contrast echocardiography in prioritizing these patients by identifying those with NSTEMI and angiographically severe coronary artery disease (CAD). Echocardiography was performed before coronary angiography in 110 patients with NSTEMI (67 ± 12 years old, 31% women). Segmental myocardial perfusion and wall motion was scored using a 17-segment left ventricular model. CAD was assessed by quantitative coronary angiography. In the total study population, median troponin T level was 0.27 μg/L (0.13 to 0.86) and Thrombolysis In Myocardial Infarction risk score 3.1 ± 1.5. By quantitative coronary angiography 15% had normal coronary angiographic findings, whereas 1-, 2-, and 3-vessel disease were present in 35%, 27%, and 23%, respectively. Severe CAD (left main stem stenosis, 3-vessel disease, or multivessel disease including proximal stenosis in left anterior descending artery) was found in 42%. Number of segments with hypoperfusion increased with CAD severity from 4.1 ± 2.0 in patients with normal coronary arteries to 5.9 ± 2.4, 7.8 ± 3.5, and 10.4 ± 2.8 in patients with 1-, 2-, and 3-vessel disease, respectively (p<0.01). In multiple logistic regression analysis risk of severe CAD increased by 39% for every additional hypoperfused segment by echocardiography independent of wall motion abnormalities and Thrombolysis In Myocardial Infarction risk score. In conclusion, contrast echocardiography may be used for prediction of angiographic CAD severity in patients with NSTEMI awaiting coronary angiography.

Aortic root dimension and arterial stiffness in arterial hypertension: the Campania Salute Network.

Objectives: The relation between aortic root dimension (ARD) and measures of arterial stiffness is uncertain. Accordingly, we studied the relation between ARD and an estimate of arterial stiffness in 12 392 hypertensive patients (age 53 ± 12 years, 43% women) free of prevalent cardiovascular disease and with ejection fraction at least 50%, from the Campania Salute Network Registry. Methods: Echocardiographic ARD was measured and compared with the value predicted by age, sex and height by using a z-score. Arterial stiffness was assessed by the pulse pressure/stroke index. The highest population tertile of pulse pressure/stroke index was considered ‘high arterial stiffness’. Results: High arterial stiffness was more common in women than in men (P < 0.001) and associated with older age, diabetes, longer duration of hypertension and less frequent smoking habit (all P less than 0.01). Patients with high arterial stiffness had smaller ARD, higher carotid intima–media thickness and plasma cholesterol, and lower BMI and glomerular filtration rate (all P less than 0.01). In multivariable logistic analysis, high arterial stiffness was associated with both lower ARD z-score [OR 0.83 (95% confidence interval 0.79–0.88)] and higher carotid intima–media thickness [OR 1.36 (95% confidence interval 1.26–1.47); both P less than 0.0001], independent of significant associations with age, female sex, body size, DBP, heart rate, duration of hypertension, diabetes and smoking habit. Conclusion: Small ARD, together with atherosclerotic modifications of conduit arteries, is associated with increased 2-element Windkessel model of arterial stiffness in hypertension, independently of the significant effect of confounders.

Myocardial Contrast Echocardiography in Assessment of Stable Coronary Artery Disease at Intermediate Dobutamine-Induced Stress Level

Background: Myocardial contrast stress echocardiography (stress MCE) is a novel method for diagnosing coronary artery disease (CAD). Few studies have compared the diagnosis of ischemia by stress MCE to angiographic CAD. Methods: Dobutamine stress MCE and SonoVue contrast infusion were performed before an elective percutaneous coronary intervention in 37 patients (8 women) aged 45–75 years with symptomatic CAD and at least one significant coronary artery stenosis measured by quantitative coronary angiography (QCA). The total and regional perfusion and wall motion (WM) were scored as normal or abnormal and attributed to the three main epicardial coronary arteries using a 17‐segment left ventricular model. Results: An intermediate stress level was obtained in 29 (78%) patients, and 2 (5%) patients obtained peak stress. A perfusion defect was detected in 92% and WM abnormality in 57% of the patients at peak stress (P < 0.01). By perfusion, 70% of stenoses were both detected and correctly anatomically located, compared to 42% by WM (P < 0.01). All 21 patients with multivessel disease and/or proximal left anterior descending (LAD) stenosis measured by QCA were identified by stress‐induced perfusion defects, while only 11 of them were identified by WM abnormalities (P < 0.01). Conclusion: Perfusion scoring is superior to WM scoring during stress MCE for diagnosing significant CAD in patients obtaining intermediate stress level, in particular, when multivessel disease or proximal LAD stenosis is present.

Impact of stroke volume on cardiovascular risk during progression of aortic valve stenosis

Objective In severe aortic valve stenosis (AS), low left ventricular (LV) stroke volume has been associated with increased cardiovascular (CV) mortality, but this association has not been explored during progression of AS in a large prospective study. Methods In 1671 patients from the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study, the association of stroke volume indexed for body surface area (SVI) with major CV events during a median of 4.3-year follow-up was assessed in Cox and time-varying Cox regression analyses. Low SVI was defined as <35 mL/m2. Results Peak aortic jet velocity in the total study population was 3.1 ±0.7 m/s. Low SVI was found in 23% at baseline and associated with higher age, body mass index (BMI), heart rate and global LV load, and with lower mean aortic gradient, aortic valve area index, energy loss index, LV mass and ejection fraction and more often inconsistent AS grading (all p<0.05). A 5 mL/m2 lower SVI at baseline was associated with higher HRs of major CV events (n=544) (HR 1.09, 95% CI 1.05 to 1.13, p<0.001) and higher total mortality (n=147) (HR 1.08, 95% CI 1.01 to 1.16, p=0.038), independent of age, sex, atrial fibrillation, mean aortic gradient, LV ejection fraction, LV mass, BMI and study treatment. Adjusting for the same covariates, low SVI at baseline and in-study low SVI were also associated with increased rate of major CV events. Conclusion In patients with AS in the SEAS study, lower baseline SVI was associated with higher HR of major CV events and total mortality independent of major confounders. Trial registration number NCT00092677: Results