Clinical trial NCT04627987: Mechanisms of Excess Risk in Aortic Stenosis
Official title: Mechanisms of Excess Risk in Aortic STEnosis After Aortic Valve Replacement
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Aortic Stenosis
Non-Sustained VT
Heart Failure
Keywords: Late gadolinium enhancement
Tissue characterisation
Arrhythmia
Sudden cardiac death
Heart failure
Aortic stenosis
Myocardial remodelling
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: Barts & The London NHS Trust
First posted: 2020-11-13
Enrollment: 192
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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%.

Primary outcomes:
measure: Heart failure death or hospitalisation for heart failure.
timeFrame: 5 years after aortic valve replacement
measure: Burden of non-sustained VT
timeFrame: 2.5 years after aortic valve replacement.
Secondary outcomes:
measure: All-cause mortality (all-cause and cardiovascular via NHS spine/death registration)
timeFrame: 5 years after aortic valve replacement
measure: change in functional capacity (6-minute walk test)
timeFrame: At 6 weeks and 12 months after aortic valve replacement.
measure: Heart failure symptoms
timeFrame: At 6 weeks and 12 months post aortic valve surgery
measure: Heart failure symptoms
timeFrame: At 6 weeks and 12 months post aortic valve surgery
measure: Burden of other serious arrhythmias requiring change in management
timeFrame: 2.5 years after aortic valve replacement
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Barts Heart Centre
Study officials:
References: