Mechanisms of Excess Risk in Aortic Stenosis (MASTER)

Mechanisms of Excess Risk in Aortic STEnosis After Aortic Valve Replacement

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Aortic Stenosis; Non-Sustained VT
• Intervention / Treatment: 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

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
• Enrollment (Anticipated): 192

Contacts and Locations

• Study Contact: Name: Thomas A Treibel, MBBS PhD; Phone Number: 020 3416 5000; Email: thomas.treibel.12@ucl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • Recruiting
    • Barts Heart Centre
    • Contact: Thomas Treibel, MBBS PhD; Phone Number: 020 3416 5000; Email: thomas.treibel.12@ucl.ac.uk
    • Principal Investigator: Thomas A Treibel, MBBS PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This is a prospective single centre, observational cohort study of patients with symptomatic severe AS (n=192) undergoing clinically indicated AVR (surgical or transcatheter) and multiparametric assessment by CMR prior to AVR.

Description

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 Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Main study; 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.

Diagnostic test: Cardiac MRI scan; Cardiac MRI scan pre- and post- aortic valve replacement to assess degree of left ventricular remodelling, fibrosis and myocardial blood flow.; Diagnostic test: Serum biomarkers (High sensitivity troponin, NT-proBNP; Blood tests looking evidence of cardiac structural remodelling and function.; Procedure: Implantable Loop Recorder; Determine post-AVR arrhythmia burden; Diagnostic test: 6 minute walk test; Validated assessment of functional capacity - distance walked over 6 minute time frame.; Diagnostic test: Echocardiogram; Ultrasound assessment of heart structure and function. Standard of care in valve surgery pathway.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality (all-cause and cardiovascular via NHS spine/death registration)		5 years after aortic valve replacement
change in functional capacity (6-minute walk test)		At 6 weeks and 12 months after aortic valve replacement.
Heart failure symptoms	New York Heart Association (NYHA) functional classification (NYHA 1 least symptomatic, 4 most symptomatic)	At 6 weeks and 12 months post aortic valve surgery
Heart failure symptoms	World Health Organisation Disability Assessment Schedule 2.0 (Higher score indicates greater disability)	At 6 weeks and 12 months post aortic valve surgery
Burden of other serious arrhythmias requiring change in management	Participants with complete heart block, Mobitz 2 AV block, new onset atrial fibrillation	2.5 years after aortic valve replacement

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: Barts & The London NHS Trust

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 23, 2021
• Primary Completion (ANTICIPATED): December 1, 2025
• Study Completion (ANTICIPATED): December 1, 2025

Study Registration Dates

• First Submitted: November 6, 2020
• First Submitted That Met QC Criteria: November 11, 2020
• First Posted (ACTUAL): November 13, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 30, 2021
• Last Update Submitted That Met QC Criteria: April 27, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Arrhythmia; Heart failure; Sudden cardiac death; Aortic stenosis; Late gadolinium enhancement; Tissue characterisation; Myocardial remodelling
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Heart Failure; Aortic Valve Stenosis; Constriction, Pathologic
• Other Study ID Numbers: 125312

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No