Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study)

Low-flow, low-gradient (LF-LG) aortic stenosis (AS) may occur with depressed (i.e. Classical
LF; CLF) or preserved (i.e. Paradoxical LF; PLF) LV ejection fraction (LVEF) and both
situations are amongst the most challenging encountered in patients with valvular heart
disease. Although, CLF-LG AS is recognized has an important clinical entity, current
ACC/AHA-ESC guidelines however do not provide precise recommendations for clinical management
of these patients because there is an important lack of data on this condition. PLF-LG AS is
a new entity recently described by our group, which is characterized by more pronounced LV
concentric remodeling with smaller LV cavity size and a restrictive physiology leading to
impaired LV filling, altered myocardial function, and a low-flow state. Up to recently, this
entity was often misdiagnosed, leading to underestimation of AS severity and inappropriate
delays for aortic valve replacement surgery (SAVR). The two main challenges in patients with
CLF- or PLF- LG AS are to distinguish between a true-severe (TS) versus a pseudo-severe (PS)
stenosis and to accurately quantify the extent of myocardial impairment. Unfortunately, the
traditional resting and stress echocardiographic parameters currently used to assess the
severity of valvular and myocardial dysfunction in patients with LF-LG AS are far from being
optimal, and as a consequence, quantification of disease severity and therapeutic management
may not be appropriate in a substantial proportion of these patients. Furthermore, it remains
uncertain which is the optimal timing and mode of treatment (SAVR vs. Transcatheter Aortic
Valve Implantation [TAVI] vs. Medical) for the different subsets of patients with LF-LG AS
patients (CLF- vs. PLF- LG AS; TS vs. PS AS; absence vs. presence of myocardial contractile
reserve etc.) THE GENERAL OBJECTIVES of the TOPAS study are to develop and validate new
parameters and biomarkers to improve the assessment of stenosis severity and myocardial
impairment, the risk-stratification, and the clinical decision making in patients with LF-LG
AS and to assess the impact of the different therapeutic strategies on patient outcomes.

THE SPECIFIC AIMS of the phase III of the TOPAS study are: (1) To obtain and analyze the
parameters of stenosis severity and LV functional impairment measured by stress
echocardiography (SE), the degree of valvular calcification measured by multidetector
computed tomography (CT), the extent of myocardial fibrosis measured by magnetic resonance
imaging (MRI), the blood levels of natriuretic peptides and markers of extracellular matrix
(ECM) turn-over, and the occurrence of clinical events in a series of 310 patients with
CLF-LG AS (210 in TOPAS- I and II + 100 in TOPAS-III) and in a series of 380 patients with
PLF-LG AS (80 in TOPAS II + 300 in TOPAS-III). (2) To measure the weight and calcification of
the valves explanted from the patients who will undergo SAVR during follow-up in order to
corroborate the actual severity of the stenosis. (3) To assess the usefulness of: i) the
projected aortic valve area measured by SE to separate TS from PS AS and predict outcomes in
PLF-LG AS; ii) the amount of valvular calcium measured by CT to separate TS from PS AS and
predict outcomes in CLF- and PLF- LG AS; iii) the myocardial contractile reserve measured by
SE, the extent of myocardial fibrosis measured by MRI, and the plasma levels of BNP and ECM
biomarkers to predict operative (SAVR) / procedural (TAVI) risk as well as hemodynamic (LV
function), functional (DASI and 6-min walk test distance), and clinical (morbidity-mortality)
outcomes in CLF- and PLF- LG AS. (4) To compare the different modes of treatment (SAVR, TAVI,
Medical), with respect to hemodynamic, functional, and clinical outcomes.

RELEVANCE OF THE STUDY: There have been very few prospective studies performed until now in
patients with LF-LG AS and these studies have included a relatively small number of patients,
have often used only one imaging modality (Doppler-echo) and a limited number of biomarkers,
and they have generally not included the patients with PLF-LG AS. Our prospective study is
the first of its kind, as it will use a complementary multimodality imaging approach and it
will measure prospectively conventional parameters of disease severity as well as new
emerging parameters and biomarkers developed by our team in large prospective series of
patients with CLF- and PLF- LG AS. This study shall contribute to improve the diagnostic
evaluation and clinical conduct in patients with LF-LG AS. This new knowledge will lead to
the establishment of clinical guidelines for the management of these high-risk patients.

Inclusion Criteria:

- LVEF≤ 40%

- Indexed aortic valve area (AVA) ≤ 0.6 cm²/m²

- Mean transvalvular gradient < 40 mmHg

Exclusion criteria:

- Pregnant or lactating women

- advanced renal failure

- tumor with metastasis