Concomitant hypertension is common among patients with AS, being found in up to 86% of patients in previous studies
[1–5]. As recently demonstrated, hypertension in asymptomatic mild-to-moderate AS is associated with reduced arterial compliance, more subclinical atherosclerosis and increased incidence of ischemic CV events as well as a 2-fold higher mortality from all causes
. Our study is the first large prospective analysis of the importance of evaluating combined LV load from valvular and arterial disease by use of non-invasive valvulo-arterial impedance in mild to moderate asymptomatic AS. In particular, the current results contribute to phenotypic characterization of patients with high global LV load in milder degrees of AS, as well as demonstrating the impact of global LV load in prediction of major CV events beyond that provided by presence of hypertension and other well established prognosticators in asymptomatic AS like AS severity and LV ejection fraction
Predictors of high global LV load
The present results add to previous knowledge by demonstrating that also in milder, asymptomatic AS, high global LV load is associated with a high risk phenotype including female gender, older age, concomitant hypertension and reduced LV systolic function, independent of an association with more severe AS by conventional measures like peak aortic jet velocity, mean aortic gradient or aortic valve area. Our finding that older age was associated with higher global LV load is consistent with the consequences of vascular aging
. Physiological aging is indeed associated with both increased vascular and ventricular stiffness
[29, 30]. The pathophysiological foundation for this finding is uncertain, but multiple mechanisms have been proposed, including reduced endothelial function, modulation of collagen, neurohumoral signaling and vascular remodeling
Consistent with previous reports,
 hypertension was a frequent finding among SEAS patients, and associated with reduced arterial compliance and higher global LV load
. The association between higher global LV load and female gender is in agreement with previous findings by Gatzka et al. showing that the observed increased arterial stiffening in women is independent of posture
The negative association between global LV load and LV ejection fraction is in line with previous studies reporting increased global LV load to be associated with reduced LV systolic function assessed by midwall shortening or longitudinal strain
[33–35]. In treated hypertensive patients, lower LV systolic function has been associated with presence of subclinical coronary artery disease
. Of note, 57% of hypertensive patients in the present study population were treated. Our findings suggest that among patients with milder, asymptomatic AS, the phenotype associated with increased global LV load is typically that of an elderly, hypertensive woman with reduced LV systolic function.
Global LV load and prognosis in AS
Confirming our hypothesis, global LV load predicted an increased rate of major CV events, in particular aortic valve events, independent of hypertension. As previously reported from the SEAS study, concomitant hypertension primarily predicted increased risk of ischemic CV events and mortality
. Of note, high global LV load predicted a statistically significant 49% increased rate of major CV events and a 55% increased rate of aortic valve events independent of other features of the high global LV load phenotype, including higher age, female gender, concomitant hypertension, and LV ejection fraction as well as abnormal LV geometry
[10, 12]. While the association with these well-known prognostic factors explained the increased mortality attributed to high global LV load in univariate analysis, also after further adjustment for different measures of AS severity, higher global LV load independently predicted a 35% higher rate of major CV events and a 41% increased rate of aortic valve events. These findings suggest that global LV load brings complementary prognostic information in patients with mild to moderate asymptomatic AS without otherwise known CV disease or diabetes.
Our findings expand observations from a retrospective study by Hachicha et al. in 544 patients with asymptomatic moderate AS
. In their study, a valvuloarterial impedance > 3.5 mmHg/ml/m2 predicted increased 4-year mortality, while the present study defined high global LV load as valvuloarterial impedance >5.00 mmHg/ml/m2. Of note, the present results add to the finding by Lancellotti et al. from a prospective study in 163 patients with asymptomatic, moderate to severe AS, that higher global LV load predict rate of major CV events independent of peak aortic jet velocity, while longitudinal deformation and left atrial area index were not assessed in the present study
. Furthermore, our findings expand the results from a small study by Zito et al. in 52 patients with severe asymptomatic AS and normal LV ejection fraction reporting that combined increased global LV load and reduced global longitudinal speckle strain were the best predictors of combined development of symptoms, aortic valve replacement and death
. In contrast, no improvement in risk prediction by global LV load was demonstrated in a multicentre study by Levy et al. in patients with low ejection fraction, low gradient severe, symptomatic AS
It has been suggested that calculating global LV load using central systolic blood pressure might yield better prediction of adverse outcome. Central blood pressure was not recorded in the SEAS trial. However, the use of central instead of brachial aortic blood pressure did not increment the predictive ability of global LV load in a recent publication
The present study was not designed to assess the effect of different types of medication on the progression of global LV load. 68% of hypertensive SEAS patients were on blood pressure-lowering medication. However, at baseline, no difference in use of different classes of antihypertensive agents was found between patients with lower vs. higher global LV load. Although the study had high power to detect a difference in incidence of major CV events, including total mortality, the study did not have statistical power to detect the observed 20% difference in ischemic CV event incidence between the groups. Thus, a type 2 error cannot be excluded for the lack of association between high global LV load and rate of ischemic CV events in the present study.