Low-flow Low-gradient Aortic Stenosis - Diagnostic Usefullness of Ivabradine
When the triad of reduced valve area (<1.0 cm\n2), high trans-valvular meangradient (>40 mmHg) and preserved left ventricular (LV) ejection fraction (EF) (>50%) is not present, the diagnosis of severe aortic stenosis is often challenging. The recommended test in this situation is a Dobutamine stress-echocardiography, but up to 30% do not increase their SV on Dobutamine, limiting the interpretation of the test. We hypothesize that in patients with low-flow low-gradient severe aortic stenosis, the oral administration of Ivabradine is safe, leads to an increase in stroke volume and may be able to differentiate patients with true severe aortic stenosis from pseudo-severe aortic stenosis\n
When the triad of reduced valve area (<1.0 cm2), high trans-valvular meangradient (>40 mmHg) and preserved left ventricular (LV) ejection fraction (EF) (>50%) is present, the diagnosis of severe aortic stenosis (AS) may be straightforward. However, a significant proportion of patients with severe AS present with low valvular gradients as a consequence of reduced LV stroke volume (SV) an entity termed low-flow low-gradient severe AS. In this subset of patients, it may be difficult differentiating between only moderate AS (pseudo-severe AS) from truly-severe AS. If severe, an increase in SV will unmask the high gradient. An increase in SV can be achieved with inotropic agents that increase cardiac contractility, which traditionally has been done in these patients using inotropic agents with beta receptor stimulating effects. The use of Dobutamine has thus generally been recommended in patients with low-flow low-gradient AS and reduced LVEF.
In case of extensive LV remodeling leading to small LV chambers with low compliance SV may also be reduced leading to low gradient severe AS despite normal LVEF. Although not extensively studied, the use of Dobutamine may increase SV in patients with low-flow low-gradient AS with preserved LVEF, and aid identification of true severe AS.
Although Dobutamine administration with gradually increase of dosage to 20 µg/kg/min during continuous echocardiography is recommended in patients with low gradient AS it is well known that up to 30% do not increase their SV on Dobutamine, limiting the interpretation of the study. In addition, Dobutamine causes peripheral vasodilatation, may lead to subvalvular obstruction and induce potential serious ventricular and atrial arrhythmias.
Ivabradine is a novel drug inhibiting the If-receptor, leading to a reduced heart rate without the negative inotropic effects of Beta-blockers. The reduction in heart rate, prolongs diastole thereby increasing LV filling, and increasing LV SV. Thus in theory a reduction in heart rate with Ivabradine may increase SV and help to differentiate pseudo-severe AS from true-severe AS in both patients with reduced and preserved LVEF, without the limitations of Dobutamine. In patients with heart failure the use of Ivabradine has been demonstrated to be safe with no adverse hemodynamic responses, however no studies have demonstrated the safety of Ivabradine in patients with severe AS. The purpose of this study is to examine the safety and feasibility of oral admission of 15 mg Ivabradine to patients with low-flow low-gradient severe AS and to compare the ability of Ivabradine with Dobutamine in differentiating true-severe AS from pseudo-severe AS.
Description of the cohort
The study is a prospective single center study, where we aim to include 25 adult patients with low-flow (stroke volume index<35 ml/m2) low-gradient (meangradient <40 mmHg) aortic stenosis with aortic valve area under <1,0 cm2 and left ventricular ejection fraction < 50 %. Patients followed at the Department of Cardiology at Odense University Hospital will be offered participation in the study.
Patients with significant concomitant valvular desease, chronic atrial fibrillation, sinus node dysfunction, bradycardia < 60 BPM, hypotension < 90/50 mmH, concomitant treatment with diltiazem or verapamil or liver dysfunction with ALAT twice upper limit of normal are excluded.
Data and biological material
Basic demographic data including medical history, medicine status, smoking, NYHA- and CCS-classification are obtained at baseline.
Comprehensive Dopler echocardiography is performed at baseline and 4 hours after the administration of Ivabradine. Focused echocardiography is performed at Dobutamine 10 and 20 µg/kg/min and hourly there after until 4 hours after the administration of Ivabradine.
Invasive hemodynamic is measured at Baseline, Dobutamine 10 and 20 µg/kg/min and hourly there after until 4 hours after the administration of Ivabradine.
We register all serious Adverse Events (SAE), Adverse events (AE) and Adverse Drug Reactions according to GCP guideline.\n
Collaborating researchers and departments
Department of Cardiology, Odense University Hospital
- Professor Jacob E. Møller, MD, PhD, DMSc
- Jordi S. Dahl, MD, PhD
Department of Cardiothoracic Anestehesia, Odense University Hospital
- Henrik Schmidt, MD, PhD, DMSc