Mechanisms of Excess Risk in Aortic Stenosis

Brief Title

Mechanisms of Excess Risk in Aortic Stenosis

Official Title

Mechanisms of Excess Risk in Aortic STEnosis After Aortic Valve Replacement

Brief Summary

      Aortic stenosis (AS) is caused by narrowing of one of the main heart valves. Replacing the
      valve is the only treatment to prevent the heart from failing or death. The timing of
      replacement is currently often too late - half of patients are left with permanent scarring
      and a quarter die within 3.5 years.

      Studies are underway to see if earlier replacement makes a difference. But for those with
      scarring of the heart, there is currently no tailored treatment. I want to change this by
      understanding why and how patients with scar are dying and what the investigators can do to
      prevent this.

      In this study, the investigators will use a heart scan (MRI) to detect scarring before valve
      replacement. After replacement, patients will receive a tiny monitor (paper clip size), which
      the investigators inject underneath the skin. This monitor continuously checks the heartbeat
      and can detect increased body fluid due to heart failure. The investigators will monitor
      patients for an average of 3 years to see if scarring is linked to abnormal heart rhythms and
      heart failure.

      Once the investigators know how and why, the investigators can target patients with available
      medications and design studies using specialised treatments, eg defibrillator implantation,
      to protect patients with scar from dying.

Detailed Description

Valvular heart disease (VHD) affects around 1.5 million people above the age of 65 across the
UK and is set to nearly double by 2050. Aortic Stenosis (AS) is the most common VHD in the
UK, affecting 3% of those over 75 with more than 11,000 people requiring aortic valve
replacement (AVR) in the UK each year (>100,000 world-wide). Current guidelines recommend AVR
to improve survival and symptom status when AS symptoms emerge or there is a reduction in
left ventricle (LV) function (1), but years of excessive haemodynamic load result in an "AS
cardiomyopathy" with LV hypertrophy, remodelling, diffuse and focal scar. The investigators,
and others, have shown that these changes lead to an excess in morbidity and mortality, but
the mechanisms of increased risk is unclear.

Patients undergoing aortic valve replacement for severe aortic stenosis have a shorter life
expectancy compared with the general population (2). Years of excessive haemodynamic load
result in an "AS cardiomyopathy" with LV hypertrophy, remodelling, diffuse and focal scar.
The investigators and others have shown that these changes to the heart muscle are associated
with poor outcome. But the mechanism of how heart muscle damage leads to excess mortality is
poorly understood.

The proposed study will enhance our understanding of the residual risk after AVR and reveal
the modes and substrate of mortality. Heart failure and heart rhythm disturbances
(arrhythmias) are likely downstream effects of heart muscle damage, but without understanding
the mode of death (heart failure, arrhythmia or other), the investigators are unable to
target therapeutic strategies to improve outcomes.

Study Type

Observational

Primary Outcome

Heart failure death or hospitalisation for heart failure.

Secondary Outcome

 All-cause mortality (all-cause and cardiovascular via NHS spine/death registration)

Condition

Aortic Stenosis

Intervention

Cardiac MRI scan

Study Arms / Comparison Groups

 Main study

Description:  Patients with severe, symptomatic aortic stenosis will be recruited and followed up with primary outcome of heart failure death and hospitalisation (n=192). Of these, 170 will have an implantable cardiac monitor placed to detect presence and burden of non-sustained VT.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Diagnostic Test

Estimated Enrollment

Start Date

March 23, 2021

Completion Date

December 1, 2025

Primary Completion Date

December 1, 2025

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with symptomatic severe aortic stenosis referred for surgical or
             transcatheter AVR (one out of: effective orifice area [EOA] <1.0 cm2 , indexed EOA of
             0.6cm/m2, peak velocity >4.0 m/s or mean gradient >40mmHg).

        Exclusion Criteria:

          -  More than moderate valve disease other than AS

          -  Diagnosis of dilated or hypertrophic cardiomyopathy, pregnancy/breast feeding

          -  eGFR <30ml/min, CMR incompatible devices

          -  Inability to complete the protocol

          -  Other conditions that would prevent participation in the study.

          -  Adenosine perfusion will not be performed in patients with AV block, severe
             asthma/COPD or LVEF<40%.

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, 020 3416 5000, [email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations

NCT ID

NCT04627987

Organization ID

Responsible Party

Sponsor

Study Sponsor

University College, London

Collaborators

 Barts & The London NHS Trust

Study Sponsor

, ,

Verification Date

April 2021