To quantify genetic variants in a focused DCM gene panel among AF-induced cardiomyopathy (AIC) and positive/negative controls

Atrial Fibrillation (AF) is the most common heart rhythm disorder affecting 1 in 3-5 adults over 45. Although most patients tolerate AF, in some people it can weaken the main pump of the heart (left ventricle), causing heart failure. It is not known why some people develop heart failure during AF and others do not. We propose that individual vulnerability is due to specific genetic abnormalities that do not cause problems until they develop AF. These genetic abnormalities have been identified in patients who develop heart failure with the onset of other stressors, such as alcohol or pregnancy.

Our study will identify 92 patients with AF-triggered heart failure, defined by having heart failure during AF but resolved after the AF was treated using a procedure called catheter ablation. We will measure how common these genetic variations are seen in patients with AF-triggered heart failure and compare them with 184 patients who have AF but don't develop heart failure (negative comparators) and 23 patients who do develop heart failure but do not recover after AF treatment (positive comparators).We shall only test for a limited number of clearly disease-causing genetic variants to ensure cost- effectiveness and minimise the risk of identifying genes of unclear significance.

If we find a genetic association, doctors could: (1) identify patients more likely to develop weakness before the AF becomes persistent, (2) fast-track at-risk patients for catheter ablation treatment, (3) offer family screening where appropriate, and (4) avoid unnecessary testing in low-risk patients. This would directly improve care for people in East London and beyond by personalising AF treatment and preventing avoidable heart failure.

INCLUSION:

AIC (Cases):

• Age ≥18
• Persistent AF before index catheter ablation or cardioversion
• LVEF ≤40% during rate-controlled (resting HR <100bpm, mean HR on 24-hour Holter <100bpm) AF prior to index catheter ablation or cardioversion
• LVEF normalisation (LVEF ≥55%) in SR, post-catheter ablation or cardioversion (≥3 months post-catheter ablation or cardioversion), no AF (>30 seconds of continuous AF) detected outside blanking period (8 weeks post-catheter ablation), and with no new introduction of any new or increased dose of heart failure guideline-directed medical therapy (GDMT) (renin-angiotensin-aldosterone system inhibitors (RAASi), Sodium Glucose Co-transporter 2 (SLGT2) inhibitors, increased dose of beta-blocker (BB), mineralocorticoid receptor antagonist (MRA))

AF-pEF (Negative controls):

• Age ≥18
• Persistent AF before index catheter ablation or cardioversion
• LVEF ≥55% during rate-controlled (resting HR <100bpm) AF. AIC-genotyping study, v1.7, 27.01.26 Page 13 of 28

AF/HF non-responders (Positive controls)

• Age ≥18
• Persistent AF before index catheter ablation or cardioversion
• LVEF ≤40% during rate-controlled (resting HR <100bpm) AF before index catheter ablation or cardioversion.
• Persistent LVSD (LVEF ≤40%) in SR, post-catheter ablation or cardioversion (≥3 months post-catheter ablation or cardioversion), no AF (>30 seconds of continuous AF) detected outside blanking period (8 weeks post-catheter ablation) and with no change in heart failure GDMT (RAASi, SGLT2 inhibitors, increased dose of BB, MRA).

EXCLUSION:

AIC (Cases).

• No alternative cause for LVSD (ischemic cardiomyopathy/non-ischaemic cardiomyopathy before AF diagnosis, primary valve disease, inherited cardiomyopathy
• Any pregnancy during AF or in the 12 months preceding LVSD onset.
• Alcohol intake >21 units/week
• Any history of cardiotoxic chemotherapy

AF-pEF (Negative controls)

• No known cause for LVSD (ischemic cardiomyopathy/non-ischaemic cardiomyopathy before AF diagnosis, primary valve disease, inherited cardiomyopathy).
• Any pregnancy during AF or in the 12 months preceding LVSD onset.
• Alcohol intake >21 units/week.
• Any history of cardiotoxic chemotherapy.

AF/HF non-responders (Positive controls)

• No alternative cause for LVSD (ischemic cardiomyopathy/non-ischaemic cardiomyopathy before AF diagnosis, primary valve disease, inherited cardiomyopathy).
• Any pregnancy during AF or in the 12 months preceding LVSD onset.
• Alcohol intake >21 units/week.
• Any history of cardiotoxic chemotherapy.

The study population is patients with a diagnosis of persistent AF who have undergone AF CA. Their LVEF at baseline and after CA in Sinus rhythm will determine eligibility. Barts Heart Centre, based at St Bartholomew's Hospital is a tertiary referral centre for cardiac electrophysiology with established expertise in AF CA. This will be the single study site. The team performed approximately 1300 index procedure AF CAs in 2018. Referral for AF CA to Barts Heart Centre is through a 'hub and spoke' arrhythmia service delivery model with its surrounding hospitals. Patients will be referred to the CRF for screening from the Electrophysiology out-patients clinic alongside the referral for AF CA. Vulnerable groups shall be excluded from this study.