Novel Technologies to Improve Echocardiographic Estimates of Left Ventricular Filling Pressure in Heart Failure Combined With Atrial Fibrillation

Study Design:

This is a prospective, multicenter study of atrial fibrillation (AF) patients referred for right or left heart catheterization (RHC/LHC). The primary objective will be to develop and validate a clinically applicable algorithm combining echocardiographic and clinical parameters to differentiate normal from elevated left ventricular (LV) filling pressure (LVFP) in AF with ≥80% diagnostic accuracy. Secondary objectives will be to identify imaging predictors of abnormal pulmonary capillary wedge pressure (PCWP) elevation during exercise and to identify prognostic imaging markers associated with mortality and heart-failure outcomes over a 3-year follow-up period.

LVFP will be measured as PCWP during RHC and as LV end-diastolic pressure (LVEDP) during LHC. In cases studied during left atrial (LA) interventions, LA mean pressure will be used as a measure of LVFP. Echocardiography will be performed during, immediately before, or immediately after catheterization (≤8 hours separation, without cardiovascular medication changes). A dedicated exercise substudy will investigate imaging predictors of abnormal PCWP rise during exertion.

Recruitment of at least 400 patients is considered feasible based on experience from a previous international multicenter AF study. Patients will be recruited from 15 centers in the USA, Europe, Asia, and New Zealand over a period of 1.5 to 2 years.

Data collection:

A 12-lead electrocardiogram (ECG) and standard clinical data, including cuff blood pressure and standard blood tests with NT-proBNP, will be recorded.

Echocardiographic Imaging:

Echocardiographic measurements will be performed according to most recent American Society of Echocardiography / European Association of Cardiovascular Imaging guidelines. In addition, LA and right atrial (RA) strains will be measured. Echocardiographic recordings will be obtained by experienced investigators without knowledge of the invasive data. A core lab for echo analysis will be established. A minimum of 10 consecutive heartbeats will be recorded. Echo will be performed either simultaneously or within 8 hours of hemodynamic assessment. Equipment from different vendors will be used. Three-dimensional echocardiography will be used in selected patients.

Key Echocardiographic Views and Measurements

• Apical 4-chamber LV-focused: mitral inflow, tissue Doppler early diastolic velocity (e') (septal, lateral, average), systolic velocity (s'), isovolumetric relaxation time, LV global longitudinal strain (GLS), LV volumes and ejection fraction, LV mass
• Apical 4-chamber LA-focused: pulmonary vein Doppler (S and D velocities and their velocity-time integrals), LA strain, LA volumes
• Apical 5-chamber: aortic valve continuous-wave (CW) Doppler
• Apical 2- and 3-chamber: LV GLS, focused LV/LA imaging
• Right ventricular / pulmonary artery evaluation: tricuspid regurgitation velocity, right ventricular outflow tract (RVOT) pulsed-wave Doppler, RVOT acceleration time
• Subcostal inferior vena cava (IVC) view: IVC diameter and collapsibility.
• RA-focused view: RA reservoir strain

Cardiac Catheterization:

LVFP >15 mmHg will be considered elevated. LVFP will be averaged over 10 beats during end-expiration, using an index beat approach for selection of heart cycles.

Bicycle ergometer in supine position with simultaneous RHC will be performed in patients scheduled for this procedure as part of a diagnostic work-up and will be performed according to current clinical routine. This includes pressure measurements and focused echocardiographic study at rest and at peak exercise. The rate of pedaling will be 60 rotations per minute, and the workload will increase gradually to a moderate level.

Outcome Data:

All-cause mortality and heart failure hospitalizations will be the primary clinical outcomes. Outcome analysis will be extended to 3 years of follow-up.

Data Management and Analysis:

All imaging and invasive pressure measurements will be analyzed with investigators blinded to the corresponding data. Echocardiography will be reviewed centrally at the Echo Core Laboratory. Statistical analyses will include descriptive statistics, logistic regression, receiver operating characteristic curve analysis, and supervised machine-learning methods to derive a diagnostic algorithm. A two-sided P value <0.05 will be considered statistically significant.

Study Flowchart:

1. Screening → 2. Consent → 3. Clinical assessment \& ECG → 4. Echocardiography → 5. RHC/LHC (± exercise) → 6. Data transfer to core labs → 7. Follow-up → 8. Analysis