Mechanisms of Excess Risk in Aortic Stenosis

Recruiting

• Conditions: Aortic Stenosis; Non-Sustained VT; Heart Failure
• Interventions: Diagnostic Test: Cardiac MRI scan; Diagnostic Test: Serum biomarkers (High sensitivity troponin, NT-proBNP; Procedure: Implantable Loop Recorder; Diagnostic Test: 6 minute walk test; Diagnostic Test: Echocardiogram

• Registration Number: NCT04627987
• Lead Sponsor: University College, London

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 Timeline

• Study First Submitted: 2020-11-06
• Study First Submitted QC: 2020-11-11
• Study First Posted: 2020-11-13
• Study Start: 2021-03-23
• Status Verified: 2021-04
• Last Update Submitted: 2021-04-27
• Last Update Posted: 2021-04-30
• Primary Completion: 2025-12-01
• Study Completion: 2025-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 192

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%.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Main study	Serum biomarkers (High sensitivity troponin, NT-proBNP	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.
Main study	6 minute walk test	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.
Main study	Implantable Loop Recorder	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.
Main study	Echocardiogram	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.
Main study	Cardiac MRI scan	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.

Primary Outcome Measures

Name	Time	Method
Heart failure death or hospitalisation for heart failure.	5 years after aortic valve replacement
Burden of non-sustained VT	2.5 years after aortic valve replacement.	As assessed on implantable cardiac monitor (approximate battery life 2.5 years)

Secondary Outcome Measures

Name	Time	Method
All-cause mortality (all-cause and cardiovascular via NHS spine/death registration)	5 years after aortic valve replacement
Heart failure symptoms	At 6 weeks and 12 months post aortic valve surgery	World Health Organisation Disability Assessment Schedule 2.0 (Higher score indicates greater disability)
Burden of other serious arrhythmias requiring change in management	2.5 years after aortic valve replacement	Participants with complete heart block, Mobitz 2 AV block, new onset atrial fibrillation
change in functional capacity (6-minute walk test)	At 6 weeks and 12 months after aortic valve replacement.

Trial Locations

Locations (1)

Barts Heart Centre; 🇬🇧 London, United Kingdom