Predicting Aortic Stenosis Progression by Measuring Serum Calcification Propensity
Predicting Aortic Stenosis Progression by Measuring Serum Calcification Propensity
Aortic stenosis is the most common valvular heart disease and an important public-health
 problem. Surgical or interventional aortic valve replacement are based on symptoms and
 measures of valvular and ventricular function using echocardiography.There is no uniform
 pattern of progression. Instead, marked differences not only between individuals, but also
 during the time course of the disease can be observed.

 Several prospective studies have been performed to enhance the predictability of disease
 behavior. Individually it is still prone to large errors and hard to predict aortic stenosis
 progression. Therefore, in patients with aortic sclerosis without severe stenosis, it is
 desirable to find a strong predictor of rapid disease progression. This would allow
 anticipating cardiovascular deterioration by identifying individuals at particular risk.

 Study Hypothesis

 In patients with aortic sclerosis, increased serum calcification propensity, as measured by
 the T50-Test, is related to the amount of stenosis progression in one year.
Background

 Clinical Background

 Aortic stenosis is the most common valvular heart disease and an important public-health
 problem. It is present in approximately 25% of all adults aged >65 years. Decisions about
 surgical or interventional aortic valve replacement are based on symptoms and measures of
 valvular and ventricular function using echocardiography. Such valvular affections are the
 result of a chronic progressive disease, usually starting with hemodynamically
 non-significant aortic sclerosis, and then progressing to severe stenosis over years. There
 is no uniform pattern of progression. Instead, marked differences not only between
 individuals, but also during the time course of the disease can be observed. Aortic sclerosis
 progresses to mild aortic stenosis in <15% of patients over 2 to 7 years. Once moderate
 stenosis is present (jet velocity >3 m/s), the average progression is 0.3 m/s per year, but
 still highly variable. When peak jet velocity exceeds 4 m/s, survival free from symptoms and
 valve replacement is significantly reduced.

 In the past, several prospective studies have been performed to enhance the predictability of
 disease behavior. Some determinants of rapid progression and adverse outcome have been
 identified, such as: age, gender, cardiovascular risk factors, B-natriuretic peptide,
 stenosis severity, degree of valvular calcification and others. Although it appears that
 progression is more rapid in degenerative calcific disease than congenital or rheumatic
 disease, predicting progression individually is still prone to large errors even when
 considering these determinants. Therefore, regular clinical follow-up is mandatory in
 patients with asymptomatic aortic valve affections. In patients with aortic sclerosis without
 severe stenosis, it is desirable to find a strong predictor of rapid disease progression.
 This would allow anticipating cardiovascular deterioration by identifying individuals at
 particular risk.

 Background of Tissue Calcification

 From a biochemical and histological point of view, aortic sclerosis is a valvular disease
 characterized by focal plaque-like lesions containing microscopic calcifications. Because
 calcium and phosphate concentrations in serum are near supersaturation, the balance of
 inhibitors and promoters critically influences the development of calcification. The serum
 protein fetuin-A is a major systemic inhibitor of calcification. Together with additional
 blood components, fetuin-A prevents the supersaturated calcium and phosphate from
 precipitating by forming soluble colloidal protein-mineral nanoparticles and is therefore an
 integral part of the defense system preventing calcifications. Low serum concentrations of
 fetuin-A are associated with a reduced capacity to inhibit calcification in vitro.
 Calcification takes place when this humoral line of defense is overwhelmed.

 Koos et al. showed that serum levels of the calcification inhibitor fetuin-A are associated
 with the progression of aortic valve calcifications and major adverse clinical events,
 independent of the renal function and inflammation.

 A novel in vitro blood test developed by Pasch et al. provides an overall measure of
 calcification propensity by monitoring the maturation time (T50) of calciprotein particles.
 First published clinical data indicate that the T50 test is a helpful biomarker for the
 prediction of future vascular calcifications.

 Study Endpoints

 -  Index test (parameter to be evaluated): T50-Test

 -  Comparator tests (tests to define disease status):

 Primary:

 Progression of peak aortic jet velocity over one year (m/s per year)

 Secondary:

 Progression of peak aortic jet velocity >20% in one year (dichotomized primary comparator)
 Combined endpoint: death, hospitalizations, aortic-valve replacement, heart failure, angina,
 syncope

 Inclusion Criteria

 -  Patient referred to routine clinical echocardiography at the Department of Cardiology,
 Inselspital Bern

 -  Aortic sclerosis with or without stenosis

 -  Written informed consent

 Exclusion Criteria

 The goal is to recruit a population comprising a large variety of clinical conditions.
 Exclusion criteria are:

 -  Age <18 years

 -  Aortic valve replacement scheduled within 1 year after inclusion

 -  Any aortic valvular disease other than degenerative sclerotic, bi- or unicuspid valves

 -  Known disease with expected survival <1 year

 -  Known malignant tumor

 -  Subvalvular obstruction (in LVOT) with mean pressure gradient >10mmHg

 Echocardiography

 Patients will be examined by standard echocardiography including a comprehensive assessment
 of cavity and wall dimensions, ventricular and valvular function, morphologic appraisal and
 pressure predictions. In particular, peak aortic jet velocity will be recorded using CW
 Doppler from the window yielding the highest velocity signal. Aortic stenosis severity will
 be measured using peak flow velocity (m/s). Progression will be expressed as peak flow
 velocity change per year (m/s per year). Aortic valve sclerosis will be assessed visually
 from a short axis according to Rosenhek: 1, no calcification; 2, mildly calcified (small
 isolated spots); 3, moderately calcified (multiple larger spots); and 4, heavily calcified
 (extensive thickening and calcification of all cusps).

 T50-Test The addition of calcium and phosphate to serum triggers the formation of primary
 calciprotein particles (CPP, see figures 2 and 3). As nano-suspension of calcium-phosphate,
 these particles represent a defense mechanism of the serum against calcification. Primary
 CPPs undergo spontaneous transition to secondary CPPs. The formation of these particles
 represents calcification. In the T50-Test, the time elapsed for the transformation of 50% of
 the particles is measured and is specific for individual sera.

 The blood-sample will be taken immediately after completion of the echocardiographic exam.

 Objective

 The purpose of this study in patients with aortic sclerosis with and without stenosis is to
 establish an independent predictor of progression of aortic valve obstruction using a new
 calcification propensity measure in the serum.

 Methods

 Recruitment 200 consecutive patients referred for a routine clinical echocardiographic exam
 showing varying degrees of aortic sclerosis will be included.
Inclusion Criteria:

 -  Patient referred to routine clinical echocardiography

 -  Aortic sclerosis with or without stenosis

 -  Written informed consent

 Exclusion Criteria

 -  Age <18 years

 -  Aortic valve replacement scheduled within 1 year after inclusion

 -  Any aortic valvular disease other than degenerative sclerotic, bi- or unicuspid valves

 -  Known disease with expected survival <1 year

 -  Known malignant tumor

 -  Subvalvular obstruction (in left ventricular outflow tract) with mean pressure
 gradient >10mmHg