This is a secondary analysis of data pooled from two prospective, observational studies of patients with severe AS ((4) and NCT03883490) from a single tertiary referral centre. These studies were approved by UK National Research Ethics Service (19/EM/0032) and the Local Research and Ethics committee (08/H0402/6). The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. All study procedures were performed in accordance with the approved study protocols, relevant guidelines and regualtions. Written informed consent was obtained from each participant.
Patient selection
Patients listed for surgical AVR (SAVR), as per clinical indication, were prospectively enrolled. Inclusion criteria were: > 18 years and severe AS (defined as one of the following: aortic valve area <1cm2, peak aortic velocity > 4m/s or mean pressure gradient >40mmHg). Exclusion criteria were other severe valve disease, atrial fibrillation, previous valve surgery, contraindication to CMR or an estimated glomerular filtration rate <30mL/min/1.73m2. Coronary artery disease (CAD) was defined as coronary artery luminal stenosis >50%, previous myocardial infarction, coronary artery bypass graft or percutaneous coronary intervention.
Study Procedures
All participants underwent transthoracic echocardiography and CMR (with adenosine stress perfusion if no contra-indication) at baseline and 6-12 months post-AVR. A subgroup of patients also underwent a CPET. All investigations were performed on the same day, 48 hours after discontinuing beta-blockers if having a CPET.
Blood samples
At baseline and follow up, blood was sampled for N-terminal pro-brain natriuretic peptide (NTproBNP), and renal function.
Echocardiography
Transthoracic echocardiography was performed using a Vivid 7 (GE Healthcare, Waukesha, Wisconsin) or iE33 (Philips Ultrasound, Netherlands) according to national guidelines (14, 15) by an accredited sonographer. Analysis was performed offline blinded to patient details using EchoPAC software (GE Medical systems, Little Chalfont, UK) or Xcelera (Philips Ultrasound, Netherlands).
Cardiac magnetic resonance imaging
CMR was performed using either a 1.5-T (Siemens, Avanto) or 3-T (Siemens, Skyra) scanner with retrospective ECG gating and a 6- or 18-channel phased array cardiac coil, respectively. Each participant was imaged on the same scanner using the same sequences at baseline and follow-up. Steady-state free precession cine images of the long-axis (2, 3 and 4-chamber views), aortic valve and short-axis stack of the LV were acquired. First-pass perfusion images were acquired after pharmacological vasodilatation stress with adenosine, 140-210µg/kg/min, for 3-5 minutes. First pass perfusion was assessed in 3 short axis slices at basal, mid-ventricular and apical levels, using a saturation recovery at 1.5T or dual sequence T1-weighted gradient echo sequence at 3T (16), with gadolinium-based contrast agent (0.05mmol/kg at 1.5T and 0.075mmol/kg at 3T) administered at 5mL/s. Rest imaging was performed approximately 10 minutes after stress imaging with a further dose of contrast. A further 0.1mmol/kg of contrast was given to those scanned at 1.5T, to bring the total dose to 0.2mmol/kg, whereas the total dose was 0.15mmol/kg at 3T. At least ten minutes following this, late gadolinium enhancement (LGE) images were acquired with the use of an inversion-recovery preparation, segmented gradient echo sequence.
All images were analysed blinded to participant details by a single observer (SA). Cardiac chambers volumetric quantification was performed using cvi42 (Version 5.10.1, Circle Cardiovascular Imaging, Calgary, Canada), with papillary muscles excluded from the LV mass quantification. Two experienced observers qualitatively assessed LGE images for focal fibrosis, categorized as present or absent, and infarct/non-infarct pattern. Right ventricular (RV) insertion point enhancement was not classed as pathological. Perfusion images were first assessed qualitatively for distribution of stress perfusion defects by two experienced observers. Quantitative analysis of myocardial blood flow was performed either by model independent deconvolution (17) or a machine learning approach using inline automated reconstruction and image post-processing within the Gadgetron software framework (16). For the latter, MBF was calculated using a blood tissue exchange model displayed on pixel-wise perfusion maps expressed in mL/min/g. Stress and rest MBF were derived for each of the 16 segments (apical segment excluded) of the American Heart Association segmentation model and averaged to calculate global MBF. Global MPR was defined as the ratio of stress to rest MBF. Microvascular dysfunction (MVD) was defined as MPR <2.0 (18) in the absence of known significant epicardial CAD (>50% luminal stenosis). Rest MBF was also normalised to the rate-pressure product (RPP), and corrected MPR was defined as the ratio of stress MBF to rate-pressure product–normalised rest MBF. Additionally, total MBF was calculated as stress or rest MBF x left ventricular mass (g).
Cardiopulmonary exercise testing
Physician supervised, symptom limited CPET was performed in a subset of participants using a bicycle ergometer. An incremental 1–min ramp protocol was used with workload increments calculated based on participant age, sex, height and weight (19). A 12-lead electrocardiogram was monitored continuously, and blood pressure recorded every 2 minutes. Expired ventilatory gases were analysed using an ErgoCard CPEX Test Station (Medisoft, Dinant, Belgium) to determine peak oxygen consumption (VO2). Indications for termination included limiting dyspnoea, chest discomfort or dizziness, ST segment depression of > 5mm measured 80ms after the J point, > 3 consecutive ventricular ectopic beats and a drop in blood pressure of > 20mmHg from baseline or patient fatigue.
Statistical analysis
Continuous variables were assessed for normality using graphical displays and the Shapiro-Wilk test and are expressed as mean ± standard deviation or median (interquartile range (IQR)), as appropriate. Categorical data are presented as number (percentage). Comparisons of continuous variables at baseline and follow up were performed using paired sample t-test and Wilcoxon signed rank, as appropriate, whilst Chi-squared or Fisher’s exact test were used for categorical variables. Comparisons between groups were conducted using independent samples t-test or Mann-Whitney U-test. A sensitivity analysis was conducted excluding any patients with significant coronary artery disease. The percentage change in variables from pre to post-AVR was calculated ([pre-AVR value - post-AVR value] / pre-AVR value) x100) and used as a continuous outcome variable for linear regression using pre-AVR data as input variables. Pearson’s correlations were performed to investigate associations between baseline variables, change in myocardial perfusion and peak VO2. NTpro-BNP was skewed and logarithmically transformed before regression analysis. Multivariable linear regression (enter) models were constructed to determine the associations with change in MPR. Variables were considered for multivariable analysis when they were related to the dependent variable on univariate analysis with p-values <0.1 or have known clinical significance. In cases of collinearity, the variable with historically the stronger prognostic importance or stronger statistical significance was chosen for the multivariable analysis. Statistical analysis was undertaken using SPSS, version 28.0 (IBM SPSS, Chicago, Illinois).