Diagnostic Impact of Low-dose Dobutamine Echocardiography in Low-flow Low-gradient Aortic Stenosis

Study Overview
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Brief Summary
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When aortic valve-area is <1.0cm2 and transvalvular mean-gradient is >40mmHg, the diagnosis of severe aortic stenosis (AS) is straightforward. However, some patients present with an apparently reduced valve-area, despite transvalvular-gradient <40mmHg; Low-flow, low-gradient aortic stenosis (LFLG AS). When a patient with LFLG AS also presents with LVEF <50%, guidelines recommends performing a Low-Dose Dobutamine-echocardiography (LDDE) to confirm true-severe AS. However, nearly 30% of patients with LFLG AS do not show an adequate respond to Dobutamine. More commonly, patients present with the combination of LFLG AS, despite LVEF≥50%. In this group of patients the use of LDDE remains undisclosed. The purpose of this study is to examine the safety and diagnostic usefulness of LDDE in patients with LFLG AS with LVEF≥50%. Furthermore we will examine factors associated with inadequate response to LDDE. 150 symptomatic and/or asymptomatic patients with LFLG and LVEF≥50% and a control group with LVEF<50% will be enrolled at the Department of Cardiology, OUH. Patients will undergo clinical evaluation including LDDE, blood analyses, CT-scan and cardiac Mri. Only a limited number of studies examine the possible use of LDDE in patients with LFLG AS and LVEF≥50% and no study has been performed documenting the safety and feasibility.

Official Title
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Diagnostic Impact of Low-dose Dobutamine Echocardiography in Low-flow Low-gradient Aortic Stenosis

Conditions
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Aortic Valve Stenosis, Valvular Stenosis, Valvular Heart Disease

Intervention / Treatment
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* Diagnostic Test: Dobutamine Stress Echocardiography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Age > 18 years. Signed informed consent. Exclusion Criteria: Other moderate-severe valvular heart disease. Unwilling to participate in the study. Poor echocardiographic window. Inability to follow-up due to temporary citizenship Registration Number (CPR-Number) or emigration within the study period. Pregnant women. Patients with severe chronic renal failure (eGFR<40 ml/min) will not undergo cardiac MRi or CT angiography. Known contrast allergy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Classical low-flow low-gradient aortic stenosis<br>LVEF<50% SVi < 35.0 mL/m2 Aortic mean gradient < 40 mmHg AVA < 1.0 cm2. | Diagnostic Test: Dobutamine Stress Echocardiography<br>* Change in echocardiographic 2D and doppler measurements during infusion with Dobutamine 5 µg/kg/min till max dosage of 20 µg/kg/min.<br>|
| Paradoxical low-flow low-gradient aortic stenosis<br>LVEF>50% SVi < 35.0 mL/m2 Aortic mean gradient < 40 mmHg AVA < 1.0 cm2. | Diagnostic Test: Dobutamine Stress Echocardiography<br>* Change in echocardiographic 2D and doppler measurements during infusion with Dobutamine 5 µg/kg/min till max dosage of 20 µg/kg/min.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse effects during Dobutamine infusion | The occurrence of angina pectoris, severely high systolic blood pressure >200 mmHg or ventricular premature beats Lown Grade >3 or supra-ventricular arrhythmias or tachycardia assessed by ECG. Occurrence of signs of echocardiographic subvalvular obstruction; (systolic anterior motion of the mitral leaflet (SAM), high velocities (>2 m/sec) in the LV outflow tract and late peaking systolic jet). | Dobutamine infusion, up to 30 minutes | 
| Factors associated with flow-reserve | a) Gender (male/female). | Dobutamine infusion, up to 30 minutes | 
| Factors associated with flow-reserve | b) Aortic valve calcification assessed by cardiac CT (AU). | Dobutamine infusion, up to 30 minutes | 
| Factors associated with flow-reserve | c) Myocardial fibrosis assessed by MRi (%). | Dobutamine infusion, up to 30 minutes | 
| Factors associated with flow-reserve | d) Baseline myocardial systolic and diastolic function estimated by echocardiography (Global Longitudinal Strain (%), Strain Ratesystolic (SRs), deceleration time of mitral E-wave (ms) and end-systolic wall-stress corrected LVEF (dynes). | Dobutamine infusion, up to 30 minutes | 
| Factors associated with flow-reserve | e) The ongoing use of beta-blockers (%, dosis). | Dobutamine infusion, up to 30 minutes | 
| Factors associated with flow-reserve | f) Association with outcomes (rate of AVR, hospitalization for cardiac failure, death). | Dobutamine infusion, up to 30 minutes | 
| The ability of LDDE to predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis. | Rate of AVR | 1 day til 3 years | 
| The ability of LDDE to predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis. | Hospitalization for cardiac failure | 1 day til 3 years | 
| The ability of LDDE to predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis. | All-cause mortality | 1 day til 3 years | 
| The ability of LDDE to predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis. | Cardiovascular mortality | 1 day til 3 years |