Identification of Parameters in rapId-proGression Subgroup Patients With Moderate Aortic Stenosis
Identification of Parameters in rapId-proGression Subgroup Patients With Moderate Aortic Stenosis
The investigators aim to identify all clinical, biological, echo and imagistic parameters
 that predispose to increased progression rates in a prospective observational trial which
 will include ONLY patients with moderate AS, with the complete cardiological investigational
 tools provided in 2012. Once those parameters are found, medical and interventional treatment
 could be implemented to decrease the mortality rates.
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).

 No influence on AS progression were treatment with simvastatin and ezetimibe (6),
 elprenone (25) or rosuvastatin (9) and statins (14).

 Slower progression was observed after osteoporosis (11) and bisphosphonate treatment
 (15), but studies were either too small, retrospective (11, 15) or biased (11).
 Geographical differences are evident in two papers which show that Korean patients
 progress slower than western population (12, 16).

 Data regarding the role of C-reactive protein in AS progression are controversial (10,
 13).

 We did not discuss the old studies or small series of patients with AS, some in the era
 of cardiac catheterizations (31-36), some in the early echo decades (37-41). Their
 capability to address this subject was limited by a retrospective design in most cases,
 potential selection bias, limited clinical, functional, or exercise data, the
 availability of only two data points per patient, lack of factors that predict the rate
 of hemodynamic progression and clinical outcome.

 4. Incidence of AS. Degenerative aortic valve disease evolves slowly from aortic sclerosis
 to aortic stenosis. Aortic sclerosis and stenosis are found in about 29% and 2-9%
 respectively in adults older than 65 years (4). In 5,201 subjects > 65 years, aortic
 valve sclerosis was present in 26% and AS in 2% of the entire study cohort; in subjects
 >75 years of age, sclerosis was present in 37% and stenosis in 2.6% (30). The prevalence
 of critical AS was 2.9% in the group 75 to 86 years of age in another study (42). In an
 observational study (43) which enrolled 953 subjects (aged 25-74 years), the overall
 prevalence of degenerative aortic valve disease (defined as the presence of valvular
 sclerosis, calcification, or thickening on echocardiographical examination) was 28%. The
 prevalence of degenerative aortic valve disease by age groups was the following: 7%
 (35-44 years), 19% (45-54), 30% (55-64), 38% (65-74) and 64% (75-84). There were no
 significant differences between men and women.

 Clinical factors associated with AS are similar to those associated with CAD (3, 44). Even
 though several small non-randomized studies (45, 46-49) suggested a beneficial effect of
 statins, three prospective randomized studies did not find any effect of lipid-lowering
 therapy on the progression of aortic-valve stenosis.(6, 10, 50).
Inclusion Criteria:

 -  age 21 years;

 -  native aortic valve leaflet thickening with reduced systolic opening on
 two-dimensional echocardiography and an aortic jet velocity at rest between 2.8 and
 3.1 m/s or a valve area calculated by the continuity equation of 1.7 to 1.5 cm2,
 evaluated at a heart rate between 60 and 90/ minute and at a systolic arterial
 pressure of 120-140mmHg at baseline;

 -  LVEF > 55% (calculated by modified Simpson formula).

 Exclusion Criteria:

 -  positive stress test (symptoms including dyspnoea, angina, syncope, ECG pathological
 changes, WMA);

 -  positive pulmonary disease (spirometry);

 -  heart failure;

 -  LVEF < 55%;

 -  moderate/severe aortic or mitral regurgitation or mitral stenosis, subvalvular or
 supravalvular AS, dynamic subaortic obstruction;

 -  CAD (history of MI or coronary artery stenosis on coronary angiography);

 -  active endocarditis;

 -  rhythm other than sinus rhythm;

 -  severe uncontrolled risk factors for CAD:

 -  uncontrolled DM,

 -  uncontrolled hypertension (SBP > 180mmHg),

 -  refuse to discontinue smoking,

 -  persistent hypercholesterolemia under treatment (total cholesterol > 240mg/dl);

 -  glomerular filtration rate < 30% or patient requiring dialysis;

 -  patient refusal; survival expectancy < 2 years;

 -  inability to perform physical exercise;

 -  suboptimal echo window;

 -  different types of echo machines.