Study design and participants
From November 2020 to February 2021, we conducted a prospective observational study registry with clinicaltrials.gov identifier NCT05059769. This study finally enrolled 91 patients with HFpEF in the First Affiliated Hospital of Chongqing Medical University (Fig. 1). Inclusion criteria included age > 18 years and conform to HFpEF diagnostic criteria (Left ventricular ejection fraction ≥ 50%, typical symptoms and signs of heart failure, HFA-PEFF score ≥ 5)13, whereas the exclusion criteria were secondary hypertension, severe valvular heart disease and persistent atrial fibrillation. Informed consent was obtained from the patients, and the study was approved by the institutional ethics board of the First Affiliated Hospital of Chongqing Medical University (approval NO.2020-606). Baseline clinical and demographic information was obtained from all patients. Body mass index (BMI) was calculated as weight (kg)/height (m²). 24-hour ABPM and echocardiography were carried out in all patients during hospitalization.
24-hour ABPM was performed using the Mobil-O-Graph NG (Z02505), a non-invasive ambulatory BP monitoring instrument. BP readings were obtained at 15-min intervals during the day and at 30-min intervals during the night. Of the total readings, ≥80% was considered valid. Furthermore, for the records valuable, at least 14 measurements during the daytime period or at least 7 measurements during the night or rest period were required14.
Ambulatory arterial stiffness index (AASI)
AASI is a more physiologically significant marker of arterial stiffness than a simple snapshot of pulse wave velocity or pulse pressure, which is derived from the regression slope of diastolic BP and systolic BP recorded in unedited 24 hours. Based on the 24-hour ABPM records, we calculated the regression slopes of individual patients' diastolic BP and systolic BP. The stiffer the arterial tree, the closer the regression slope and AASI are to 0 and 1, respectively1,2. AASI was obtained as follows:
AASI = 1-slope (diastolic BP/systolic BP)
The cardiac diastolic function of HFpEF was assessed by transthoracic echocardiography (Vivid E95, AU11403, GE Vingmed Ultrasound AS). Using the parasternal short-axis two-dimensional view to image the heart and record an M-mode echocardiogram at the level of the papillary muscles. Cardiac function parameters, such as left ventricular ejection fraction (LVEF), diastolic interventricular septum thickness (IVSd), diastolic left ventricular posterior wall thickness (LVPWd), left atrium volume index (LAVI), left ventricle mass index (LVMI), the peak velocity of the filling peak in the early diastolic period (E) , the peak velocity of the filling peak in the late diastolic period (A), the E/A ratio (E/A), the ratio of the early diastolic transmitral filling velocity to the early diastolic septal tissue velocity (Septal E/e’) and the ratio of early diastolic transmitral flow velocity to mitral annular velocity at the lateral wall (Lateral E/e’) were measured by the same investigator. At the same time, tricuspid annular plane systolic excursion (TAPSE) and plane contraction offset velocity of tricuspid annulus (TAPSE-S) reflecting right ventricular function were measured as well15.
Data on epidemiological information, medical history, exposure history, underlying comorbidities, symptoms, signs, laboratory, and radiological characteristics were obtained from electronic medical records. All the data were collected by two investigators independently and double checked by other investigators.
Not all patients had severe diastolic dysfunction, so in the logistic regression, we set mean E/e’ = 10 rather than 14 as the critical value. AASI = 0.52 was the cut-off point of receiver operating characteristic (ROC) curves (Fig 3). It was close to the upper normal border of AASI = 0.551,2, so we pre-specified that the patients would be divided into two groups according to the upper normal border: AASI group ≤ 0.55 group and AASI > 0.55 group.
Categorical variables were described as frequency rates and percentages, and continuous measurements as mean (standard deviation: [SD]) if they are normally distributed or median (interquartile range: [IQR)] if they are not. X2 test was used to test for differences in categorical variables among the two groups. T test or Mann-Whitney test was used to compare continuous variables according to the normal distribution or not. Spearman correlation analysis was used for assessing the correlates of left ventricular diastolic function. logistic regression analysis was used to test independent factors of left ventricular diastolic dysfunction. To explore whether AASI provides additional value in predicting impaired left ventricular diastolic function in patients with HFpEF, we performed ROC curves and tested for equality of the areas under the curves (AUC). All P values were two-tailed, and significance was set at P < 0.05. Statistical analyses were performed using SPSS software (version 22.0).