Short summary

Aortic stenosis (AS) is the most common valvular heart disease in the western world, with an incidence 2-5% in patients >65 years. The diagnosis is confirmed by echocardiographic findings of a low valve-area and high transvalvular gradients. But it is not uncommon to find a low valve-area with low transvalvular gradients, often related to a low stroke volume -Low-flow, Low-gradient (LFLG). If combined with heart failure (LVEF<50%), the diagnostic accuracy can be increased by performing a low-dose Dobutamine echocardiography (LDDE).If not (LVEF>50%), correctly diagnostics is much more difficult. The purpose of this study is to examine the safety and diagnostic usefulness of LDDE in patients with LFLG AS with LVEF>50%.

Rationale

Introduction

Aortic stenosis (AS) is the most frequent valvular heart disease in the western world. When symptomatic, severe AS has a dismal prognosis if not treated. There is currently no pharmacological therapy available to reduce the progression of AS, thus the only available treatment is aortic valve replacement either surgical (SAVR) or transcatheter (TAVR).

In AS gradual narrowing of the effective valve orifice leads to flow-acceleration and consequently the creation of a transvalvular pressure gradient. When aortic valve area is <1.0 cm2 and trans-valvular mean gradient is >40 mmHg, the diagnosis of severe aortic stenosis (AS) is straightforward.

However, a significant proportion of patients with possible severe AS present with an apparently reduced valve area despite lower than expected transvalvular gradients. This may be caused by a low stroke volume (SV) and classically also reduced left ventricular ejection fraction (LVEF <50%). In case of the latter, guidelines recommends low-dose Dobutamine echocardiography (LDDE). Dobutamine is a beta1-receptor agonistic drug able to increase LV contractility and stroke volume. Thus, LDDE may help differentiate between low-flow (LF) low-gradient (LG) true-severe AS and pseudo-severe AS by increasing stroke volume. However, nearly one third of these patients do not adequately respond to Dobutamine limiting the interpretation of the study. For these patients the operational risk of valve replacement is significantly higher.

More commonly, patients present with the combination of low-gradients and low valve area, despite preserved left ventricular ejection fraction LVEF>50%. In this context, guidelines suggest focusing on the assessment of SV. It is generally accepted that AS is not severe if SV is preserved, while AS can be severe when SV is reduced.

In the latter condition termed "paradoxical LFLG AS", most common among females, SV may be reduced despite LVEF>50% due to extensive LV remodeling leading to small LV chambers with low compliance, and subclinical reduced LV function not detected by LVEF>50%. Guidelines recommend an integrative approach, including non-contrast CT to assess aortic valve calcification and echocardiographic variables in order to classify AS severity in paradoxical LFLG AS. CT assessed aortic valve calcification has recently been recognized to demonstrate significant gender differences and consequently different thresholds have been recommended, thus correct classification may still be challenging.

Recently it has been proposed that the use of LDDE may also provide important information in patients with LFLG AS and preserved LVEF. However, there is little data regarding the use of LDDE in this setting, and risk of subvalvular obstruction during Dobutamine infusion may compromise its use this subset of patients.

The purpose of this study is to examine the safety and diagnostic usefulness of LDDE in patients with LFLG AS with LVEF?50%, by examining the occurrence of adverse events during the test and comparing its impact on diagnostic outcome to a current guideline based strategy. Furthermore we will examine factors associated with inadequate response to LDDE.

Hypothesis

LDDE in patients with LFLG AS with LVEF?50%

1) Is as safe, and similar rate of adverse effects as among patients with LFLG AS with LVEF<50%.

2) The hemodynamic response correlates with the degree of aortic valve calcification.

3) Is superior to non-contrast CT in assessing AS severity and predicting outcome and indication for AVR.

Description of the cohort

All adult patients with echocardiographic findings of Low-flow (SVi<35 ml/m2) low-gradient (mean gradient <40 mmHg) AS with estimated AVA<1.0 cm2 referred to the Department of Cardiology, Odense University Hospital, who gives informed consent. 

Patient will be exclude from the study due to; Other moderate-severe valvular heart disease, unwillingness to participate, poor echocardiographic window or inability to follow-up due to temporary citizenship Registration Number (CPR-Number) or emigration within the study period.

Data and biological material

Background data with medical history. Bloodsamples for biobank. Questionnaires (DASI, EQ-5D and KCCQ). Cardiac Non-contrast-CT and CT-Angiography (not if eGFR<40 ml/min). cardiac MRi (not if eGFR<40 ml/min). Echocardiography and low-dose Dobutamine Echocardiography.

Collaborating researchers and departments

Department of Cardiology, Odense University Hospital

• Jordi S. Dahl, Klinisk lektor, overlæge, PhD. dr.med.
• Kristian A. Øvrehus, overlæge, PhD.
• Rasmus Carter-Storch, 1.reservelæge, PhD.
• Jacob E. Møller, Professor overlæge PhD. dr.med.