Åshild E. Rieck

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).

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.

Asymmetric septal hypertrophy – a marker of hypertension in aortic stenosis (a SEAS substudy)

Abstract Background. Some patients with aortic stenosis develop asymmetric septal hypertrophy (ASH) that may influence the surgical approach and is associated with higher perioperative morbidity. The aim of this analysis was to characterize further this subtype of aortic stenosis patients. Methods. Baseline data in 1719 patients with asymptomatic aortic stenosis, participating in the Simvastatin Ezetimibe in Aortic Stenosis study evaluating the effect of combined treatment with simvastatin and ezetimibe on progression of aortic stenosis was used. The study population was divided according to presence of ASH (interventricular septal/posterior wall thickness ratio >1.5). Left ventricular (LV) hypertrophy was considered present if LV mass index ≥104 g/m² in women and ≥116 g/m2 in men. Results. ASH was present in 22% of patients and associated with higher LV mass index, total peripheral resistance and peak transaortic velocity and concomitant hypertension (all p<0.05). Thirty-four percent of patients with ASH had combined ASH and LV hypertrophy (asymmetric LV hypertrophy). These patients had higher systolic blood pressure, lower LV ejection fraction and larger left atrial diameter than patients with ASH only. In logistic regression analyses, hypertension was the most important predictor both for ASH (odds ratio, OR 1.38 [1.05–1.82]) and for asymmetric LV hypertrophy (OR 2.99 [1.71–5.25]), both p<0.05) independent of other covariates including severity of aortic stenosis. Conclusion. Hypertension is the main clinic characteristic of ASH and asymmetric LV hypertrophy in patients with asymptomatic aortic stenosis independent of severity of aortic stenosis.

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.

Pulse pressure, left ventricular function and cardiovascular events during antihypertensive treatment (the LIFE study)

Abstract Background. Pulse pressure (PP) has been related to risk of cardiovascular events in hypertension. However, less is known about modification of this risk marker during antihypertensive treatment in patients with left ventricular (LV) hypertrophy. Methods. Associations of in-treatment PP with LV systolic function and cardiovascular events was assessed in 883 patients with electrocardiographic LV hypertrophy during 4.8 years of randomized losartan- or atenolol-based treatment within the echocardiographic substudy of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Results. PP was similarly reduced by both treatments. In different multiple regression models, lower in-treatment PP was independently associated with lower in-treatment LV ejection fraction (β=0.16), stress-corrected midwall shortening (β=0.20), stroke volume (β=0.11) and cardiac index (β=0.07, all p<0.05). In time-varying Cox regression models, 10mmHg lower in-treatment PP was associated with a 28% higher rate of cardiovascular events [hazard ratio, HR = 1.28 (1.09 – 1.52), p<0.01] independent of in-treatment LV mass and ejection fraction, history of ischemic heart disease, Framingham risk score and study treatment allocation. Conclusion. During systematic antihypertensive treatment in hypertensive patients with electrocardiographic LV hypertrophy, lower in-treatment PP was associated with lower in-treatment LV function and cardiac output as well as higher rate of cardiovascular events.

Determinants of systolic blood pressure response during exercise in overweight subjects.

Abstract Aim. Higher systolic exercise blood pressure (BP) is associated with increased cardiovascular risk in hypertension. We aimed at identifying covariates of systolic exercise BP in overweight subjects. Methods. 77 subjects with body mass index (BMI) > 27 kg/m2 and without known heart disease were tested. BP was measured by sphygmomanometry before and at all exercise stages during maximal exercise capacity testing on a treadmill. High peak systolic exercise BP was defined as ≥ 200 mmHg. Results. The study population was 48 ± 10 years and included 60% women and 42% with known hypertension. Average BMI was 32.6 ± 4.8 kg/m2 and clinic BP 132/82 ± 17/8 mmHg. High systolic exercise BP was found in 32%. Subjects with high systolic exercise BP had higher systolic clinic and 24-h ambulatory BP (ABP), as well as lower peak oxygen uptake, compared with subjects with normal systolic exercise BP (all p < 0.05). In multiple regression analysis known hypertension (β = 0.33), higher systolic ABP (β = 0.22) and high-density lipoprotein (HDL)-cholesterol level (β = 0.23, all p < 0.05) predicted higher systolic exercise BP independent of sex and peak oxygen uptake (multiple R2 = 0.32, p < 0.001). Conclusion. Among overweight subjects, known hypertension, higher systolic ABP and HDL-cholesterol level were the most important factors predicting higher systolic exercise BP.

Contrast stress echocardiography in hypertensive heart disease

Hypertension is associated with atherosclerosis and cardiac and vascular structural and functional changes. Myocardial ischemia may arise in hypertension independent of coronary artery disease through an interaction between several pathophysiological mechanisms, including left ventricular hypertrophy, increased arterial stiffness and reduced coronary flow reserve associated with microvascular disease and endothelial dysfunction. The present case report demonstrates how contrast stress echocardiography can be used to diagnose myocardial ischemia in a hypertensive patient with angina pectoris but without significant obstructive coronary artery disease. The myocardial ischemia was due to severe resistant hypertension complicated with concentric left ventricular hypertrophy and increased arterial stiffness.

Left atrial volume index as a marker of left ventricular diastolic dysfunction in asymptomatic Tanzanian diabetic patients

Abstract Aim: To determine the prevalence of left atrial (LA) enlargement and its relation to left ventricular (LV) diastolic dysfunction among asymptomatic diabetic outpatients attending Muhimbili National Hospital in Dar es Salaam, Tanzania. Methods: Echocardiography was performed in 122 type 2 and 58 type 1 diabetic patients. Diastolic dysfunction was defined as peak transmitral blood velocity to medial mitral annulus velocity (E/E’) ratio ≥ 15. LA volume indexed to body surface area (LAVI) was considered enlarged if ≥ 29 ml/m2. Results: Enlarged LAVI and LV diastolic dysfunction were more common in type 2 than in type 1 diabetic patients (44.3 vs 25.9% and 20.5 vs 3.5%, respectively, both p < 0.05). In multivariate linear regression analysis, larger LAVI was associated with LV diastolic dysfunction independent of significant associations with LV mass index and presence of mitral regurgitation in type 2 diabetic patients, while LV mass index, lower ejection fraction and longer duration of diabetes were the main covariates of larger LAVI in type 1 diabetic patients (all p < 0.05). Conclusion: Enlarged LA is common among asymptomatic Tanzanian diabetic patients, and particularly associated with LV diastolic dysfunction in type 2, and with cardiomyopathy and lower systolic function in type 1 diabetic patients.