Patients
A total of 22 consecutive clinical stable patients with chronic AF (> 2 years) and severe secondary TR were enrolled between November 2017 and October 2019 at the Department of Cardiology, Aarhus University Hospital, Denmark. All patients were referred to the out-patient clinic due to heart failure symptoms for evaluation. Patients with moderate to severe left-sided valve disease, LVEF < 50% and pacemaker devices were excluded. These patients were compared with 22 patients with restrictive cardiomyopathy due to confirmed CA (determined by endomyocardial biopsy using Congo red dye and immunohistochemistry) as follows: 10 patients with wild-type transthyretin, 4 patients with familial amyloidosis mutation carriers, and 8 patients with light-chain amyloidosis.[13] All control subjects (CA patients) had a LVEF ≥ 50 % and no significant TR, 17 patients were in sinus rhythm, 5 patients were in AF and all patients with CA were without significant left-sided heart valve disease or significant TR at the time of the investigation.
Ethics
All patients were aged ≥18 years and provided written informed consent according to the principles of the Helsinki Declaration. The local scientific ethical committee of the Central Denmark Region approved the study (1-10-72-399-17).
Invasive hemodynamic assessment
Right heart catheterization (RHC) was conducted in all patients with a standard 7.5-F triple lumen Swan-Ganz thermistor and balloon-tipped catheter (Edwards Lifesciences, Irvine, CA, USA). RHC was performed through an 8-french sheath in the right internal jugular vein and advanced to the PA. The position of the catheter was assessed by the distinct pressure waveforms and fluoroscopy. At rest and at each level of exercise level until exhaustion, systolic, diastolic, mean pulmonary artery pressure (sPAP, dPAP, mPAP), mean right atrial pressure (RAP), PCWP, cardiac output (CO), were measured. Oxygen consumption (VO2) was measured using breath-by-breath expired gas analysis (Jaeger Master Screen CPX, CareFusion, 234 GmbH, Hoechberg, Germany). Arterial-venous O2 difference (A-VO2diff) was measured directly as the difference between systemic and PA O2 contents (O2 saturation x hemoglobin x 1.34). CO was calculated by direct Fick (CO = VO2/A-VO2diff). Stroke volume (SV) was calculated as CO/heart rate (HR) and indexed according to body surface area (BSA) as cardiac index (CI). Pulmonary vascular resistance (PVR) was calculated as: PVR=(mPAP-PCWP)/CO [14-16]. RV stroke work index (RWSVI) was calculated as: stroke volume index (SVI) x 0.0136 x (mPAP-mRAP) and left ventricular stroke work index as: SVI x 0.0136 x (mean blood pressure – mPCWP). Left ventricular (LV) transmural pressure (LVTMP) reflecting LV preload was calculated as PCWP-RAP.[17, 18]
Echocardiography
Transthoracic echocardiography was performed using the GE VIVID E95 system (GE Medical System, Horten, Norway) with a 3.5-MHz transducer for 2-D evaluation. We used the current guidelines for the assessment of chamber quantification.[19, 20] All measurements were averaged over 4-6 consecutive heart cycles in end-expiration. The following parameters were recorded by 2-dimensional echocardiography: LVEF, left ventricular end-diastolic (LVEDV) and systolic volume (LVESV) were assessed by the biplane disc method. Left and right atrial volume were assessed by biplane area-length method indexed by body surface area (BSA). The interventricular septum and the posterior wall thickness were obtained from the parasternal view. LV mass was calculated and indexed according to BSA. Right ventricular (RV) systolic function was assessed by the 3D-RVEF volumetric method, tricuspid annular systolic velocity (RV S´) measured by lateral, pulsed tissue Doppler velocities. In addition, tricuspid annular plane systolic excursion (TAPSE) was obtained from the lateral tricuspid plane. The tricuspid annulus was measured in a RV focused 4-chamber view and the severity of secondary tricuspid regurgitation was categorized as mild, moderate or severe based on current guidelines.[20, 21] EchoPAC version 203 (GE-Vingmed Ultrasound, Horten, Norway) was used for image analysis.
Exercise protocol
Symptom-limited exercise was performed on a semi-supine bicycle (GE eBike L Ergometer, Freiburg, Germany). Work rate started at 0W and was increased by 25W every 3 min. The level of workload was determined by each patient based on self-reporting. The patients were encouraged to maintain a fixed pedalling speed of 60-65 rounds per minute and to exercise until reaching Borg scale 20.[22] During the test, continuous 12-lead electrocardiogram and pulse oximetry were measured together with blood pressure. In order to determine oxygen uptake (VO2), gas exchange was measured using a breath-by-breath technique (Jaeger MasterScreen CPX, CareFusion, 234 GmbH, Hoechberg, Germany), Peak VO2 was defined as the averaged value during the final 15 seconds of exercise. The gas analyser was calibrated before each test.
Statistical methods
Data are reported as means ± SD for normally distributed or median (interquartile range) for non-normally distributed variables. Categorical data is presented as absolute values with percentages. Between-group differences were tested using the 2-sample independent t-test, the Mann-Whitney U-test for non-normally distributed data and χ2 test for dichotomized data. We used linear regression models to compare continuous variables and predicted value and residual to check the models. All tests were two-sided and a P value <0.05 was considered significant. Statistical analysis was performed using STATA/IC version 13.0 (STATACorp LP, College Station, TX, USA).