Predicting Aortic Stenosis Progression by Measuring Serum Calcification Propensity (PASP)

March 27, 2023 updated by: University Hospital Inselspital, Berne

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

200

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Switzerland
      • Bern, Switzerland, 3010
        • Dep. of Cardiology, Bern University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: All patients
Compare patients with high calcification propensity do have faster valve-stenosis progression
Other: no intervention
progression monitoring by echocardiography

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Progression of peak aortic jet velocity over one year (m/s per year)
Time Frame: One year
One year

Secondary Outcome Measures

Outcome Measure
Time Frame
Progression of peak aortic jet velocity >20% in one year
Time Frame: One year
One year
Combined endpoint: death, hospitalizations, aortic-valve replacement, heart failure, angina, syncope
Time Frame: One year
One year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Inselspital, Berne

Investigators

  • Principal Investigator: Stefano de Marchi, Senior Consultant, Dept. of Cardiology, University Hospital Bern, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 30, 2014

Primary Completion (Actual)

January 31, 2016

Study Completion (Actual)

February 28, 2017

Study Registration Dates

First Submitted

September 11, 2014

First Submitted That Met QC Criteria

September 11, 2014

First Posted (Estimate)

September 16, 2014

Study Record Updates

Last Update Posted (Actual)

March 30, 2023

Last Update Submitted That Met QC Criteria

March 27, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 087/14

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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