Prospective Study Focused on idEntification of cliNical, Biological and Imagistic Parameters in rapId-proGression Subgroup Patients With Moderate Aortic Stenosis

1. Why this study? 1.1. Significance and difficulty of the problem being addressed. Aortic stenosis is the most encountered valvular disease According to the 2007 ESC guidelines (1), moderate aortic stenosis (AS) is defined as valve area 1.0-1.5 cm² (0.6 cm²/m² to 0.9 cm²/m² body surface area (BSA)) or mean aortic gradient of 30-50 mmHg in the presence of normal flow conditions. We already know how to treat patients with severe AS, symptomatic or not. On the contrary, in patients with moderate AS there is not a clear agreement on what to do to reduce the excess mortality (detailed below). Why do these patients die and what can we do to reduce mortality rates? 1.2. Originality of the proposed solution and the appropriateness of the objectives. There are already some progression factors in all spectrum of AS that have been highlighted (discussed below) and which could influence mortality in this patient subgroup, but none of the studies address exclusively to moderate AS. The majority of these studies have major limitations, are not prospective, and even if some are, the parameters followed do not cover the complete cardiological investigational tools (no 3D left ventricular (LV) ejection fraction (EF), no strain, no magnetic resonance imaging (MRI), etc.). As in any major disease, lots of studies that include moderate AS are contradictory on the same matter (see progression of AS). We aim to identify all clinical, biological, echo and imagistic parameters that predispose to increased progression rates in a prospective randomized trial which will include ONLY patients with moderate AS, with the investigational tools provided in 2012. Once those parameters are found, medical and interventional treatment could be implemented to decrease the mortality rates.

But first, some data about survival and death in moderate AS. I would like to start by paraphrasing one of the most passionate researchers in the field of aortic stenosis, C. Otto (2): "even mild disease is important" (referring of course at the outcomes of patients with mild AS). Similarly, people with moderate AS/ aortic sclerosis, not even mentioning moderate to severe AS (3) have an increased death rate in comparison to age-matched healthy population. The same author reported in 1999 the results of a prospective study (4) with a follow-up (FU) at 5 years and she observed a cardiac death rate of 6.1% in general population (normal aortic valves), 10.1% in patients with aortic sclerosis and 19.6% in patients with AS. In 2004 Rosenhek et al. (5) found a cardiac death rate of 8.7% in a population with mean age of 67 years, with moderate AS at the initial examination. Even though the largest study (6) evaluating medical treatment in moderate AS reported a cardiac death rate of 6.0% (similar to general population), we consider this study not eloquent because there was a super-selected population enrolled (investigators ruled out the most important progression factors of AS: exclusion criteria included history of coronary artery disease (CAD), stroke and diabetes mellitus (DM)). 2. Trials involving patients with moderate AS. In this presentation we will not review or discuss outcomes of severe AS, but ONLY outcomes of patients with MODERATE AS.

The first step in our research was the identification of all studies involving moderate AS. We observed that there are few studies that included ONLY patients with moderate AS. At the opposite, the large majority of studies included moderate AS among all spectrum of AS patients (sclerosis, mild, moderate, severe- alone or combined). That is why we categorized all previous studies regarding moderate AS by the baseline inclusion criteria. We found 4 major groups of enrolled patients that we reviewed and discussed below: patients with mild to moderate AS (Table 1) (5-10), patients with moderate AS (Table 2)(11-12), patients with mild, moderate and severe AS (Table 3)(13-20) and patients with moderate to severe AS (Table 4)(21-27).

Even though all essential data regarding moderate AS can be easily read in the tables (patient characteristics, progression of moderate AS, outcomes, survival, limitations and conclusions) and even though progression factors are summed-up below, of great importance are the results of some echo studies recently published on which I would like to briefly discuss. Monin et al. enrolled 107 patients with baseline peak velocity (PV) of 3.5 to 4.4 m/s (26), he concluded that female sex, PV and brain natriuretic peptide (BNP) at baseline were correlated with AS progression and developed a score to best stratify outcomes in these patients (see Table 4 for limitations). Marechaux et al. (27) included 135 patients with at least moderate AS (53% had severe AS), with normal stress test at baseline. Increased progression was present in those with resting mean gradient (MG) >35 mmHg and exercise-induced increase in MG >20 mmHg (see Table 4 for limitations). Two studies tried to clarify the role of strain in AS. One of the studies showed that strain gradually decreased as severity of AS increases and that global longitudinal strain (GLS) might be useful to assess subtle changes in LV function in patients with mild, moderate and severe AS (17). In the second study, Ng et al. (19) found that longitudinal, radial and circumferential strain and strain rate (SR) deteriorate with aortic valve disease progression. Important limitations of both studies are found in Table 3. 3. Progression of AS. There is a wide variability in AS progression. Progression rates (for the PV) begin from 0.15±0.01 m/s/y in population without cardiovascular risk factors (6) and increase to 0.34±0.42 m/s/y in patients with CAD, reaching 0.45±0.38 m/s/y in patients with cardiovascular events (5).

High progressors are those that have at least one abnormal parameter of the followings: echocardiography parameters: baseline PV (3, 12, 5, 10, 16, 20, 26), baseline peak gradient (24), mean gradient (3), rate of increase in PV (3, 20), moderate to severe aortic valve calcification on echo (5, 12), LV hypertrophy (27), resting MG >35 mmHg (27), exercise-induced increase in MG >20 mmHg (27), E velocity (16), bicuspid aortic valve (16); clinical predictors: CAD (5, 21), age (>80 years-8, 12, 18, 20, >64 years-21, >65years-27), diabetes (14, 27), metabolic syndrome (MS) (24), dialysis (28, 29), increased BMI (7), functional status (3), history of smoking (7, 30), systolic blood pressure (SBP) (18, 30), male gender (24, 30), female gender (26); and biological parameters: parathyroid hormone (PTH) level (18), BNP at baseline (26), high lipoprotein (a) (Lp(a)) and low density lipoprotein (LDL) cholesterol levels (30).