Evaluation of Unattended Automated Office, Conventional Office and Ambulatory Blood Pressure Measurements and Their Correlation with Target Organ Damage in an Outpatient Population of Hypertensives: Study Design and Methodological Aspects

Abstract

Accurate measurement of blood pressure (BP) has a pivotal role in the management of patients with arterial hypertension. Recently, introduction of unattended office BP measurement has been proposed as a method allowing more accurate management of hypertensive patients and prediction of hypertension-mediated target organ damage (HMOD). This approach to BP measurement has been in particular proposed to avoid the white coat effect (WCE), which can be easily assessed once both attended and unattended BP measurements are obtained. In spite of its interest, the role of WCE in predicting HMOD remains largely unexplored. To fill this gap the Young Investigator Group of the Italian Hypertension Society (SIIA) conceived the study “Evaluation of unattended automated office, conventional office and ambulatory blood pressure measurements and their correlation with target organ damage in an outpatient population of hypertensives”. This is a no-profit multicenter observational study aiming to correlate attended and unattended BP measurements for quantification of WCE and to correlate WCE with markers of HMOD, such us left ventricular hypertrophy, left atrial dilatation, and peripheral atherosclerosis. The Ethical committee of the Federico II University hospital has approved the study.

Appendices

Appendix 1: Echocardiographic Protocol

Transthoracic Doppler-echocardiography will be performed following a standardized protocol:

• LV chamber dimensions and wall thicknesses will be measured according to the American Society of Echocardiography guidelines and LV mass calculated using a necropsy validated formula [22]. LV mass will be normalized for height to the 2.7 power and LVH will be defined as LV mass ≥ 50 g/m^2.7 in men and ≥ 47 g/m^2.7 in women [23]. Relative wall thickness will be calculated as two times the posterior wall thickness/LV diastolic diameter ratio independently of the presence of LVH and used as index of LV geometry. Index values ≥ 0.42 will be considered indicative of concentric geometry.

• LV volumes and stroke volume will be measured by the biplane method of disks and used to calculate ejection fraction (LVEF), as the primary measure of systolic function. Stroke volume will be used to estimate cardiac output. Stroke index and cardiac index will be generated by normalization for height at the respective allometric powers to account for the non-linear variations with body size [24]. Total peripheral resistance will be calculated as mean arterial pressure/cardiac index times 80.

• Tissue Doppler study (pulsed wave spectral analysis) will be used to measure peak mitral annular systolic velocity (peak S’, expressed as mean of 4 measurements obtained in septal, lateral, inferior and anterior mitral annular position), as an estimate of longitudinal LV function [25]. Peak S’ < 8.5 cm/s (10th percentile of a reference Caucasian healthy population) will be taken as indication of systolic dysfunction of LV longitudinal fibers [26].

• Diastolic function will be evaluated using transmitral and pulmonary vein pulsed wave Doppler curves and early diastolic Tissue Doppler velocity of mitral annulus (E’), according to the recommendations of the American Society of Echocardiography [27].

• Pulsed wave transmitral Doppler signal will be obtained with the sample-volume placed between the tips of mitral leaflets and in the LV outflow tract in apical four and five-chamber views to measure peak early (E) and late (A) transmitral flow velocity (cm/s) and deceleration time of E velocity (DTE) (ms), thus E/A ratio will be calculated. Tissue Doppler spectral signal will be obtained at the septal mitral annulus to measure peak E’ diastolic mitral annular velocity. The ratio E/E’ will be used to estimate LV filling pressure (normal LV filling pressure was defined as E/E’ ratio < 8) [27]. All these measurements will be averaged from 5 consecutive cycles. E/E’ ratio will be used to classify LV diastolic function together with other parameters (E/A ratio of transmitral flow, deceleration time of E and the difference in duration of atrial wave on pulmonary vein flow and atrial wave on transmitral flow and maximal left atrial volume) in 4 degrees as proposed by Redfield et al. (32): normal, mild dysfunction, moderate dysfunction and severe dysfunction. Maximal left atrial volume will be computed from 2D apical 4-chamber view using the area–length method and will be normalized for body surface area. Additional measurement will be done using ellipsoid method and indexing for height at allometric power of 2 [28].

All echocardiograms will be stored digitally in DICOM format and sent with electronic support for central reading to the ECHO core laboratory at “Hypertension Research Center” of the Federico II University of Naples.

Appendix 2: Ankle Brachial Index Protocol [29]

• Place the blood-pressure cuff on the patient’s right or left arm.

• Palpate the brachial pulse.

• Apply gel at the site where you feel the pulse, and obtain a Doppler signal by placing the probe at a 60-degree angle toward the patient’s head.

• Inflate the cuff rapidly to 20–30 mm Hg above the point of cessation of brachial-artery flow, then slowly deflate the blood-pressure cuff in order to note the systolic value.

• Wipe the gel from the patient’s skin and repeat the procedure on the other arm.

• After measuring the systolic blood pressure in the arms, place the cuff just above the ankle on the right or left leg. The anatomical landmark of the dorsalis pedis artery should be lateral to the extensor hallucis longus tendon.

• Place the Doppler probe on the palpable dorsalis pedis pulse or on the site that produces the best arterial Doppler signal from the dorsalis pedis artery.

• Once again, inflate the blood-pressure cuff to 20–30 mm Hg above the level at which flow ceases, then deflate the cuff slowly and note the systolic pressure (the pressure at which you first hear the flow from the dorsalis pedis artery).

• Repeat the procedure for the posterior tibial artery.

• Then repeat the procedure for the contralateral leg to obtain the systolic pressure from both the dorsalis pedis and posterior tibial arteries.

• To calculate the ankle–brachial index, divide the systolic blood pressure in the ankle by the systolic blood pressure in the arm. The highest brachial systolic pressure is usually chosen for calculation, simply because the vessels of an arm may be affected by arterial occlusive disease.

The highest of the systolic pressures from the dorsalis pedis or posterior tibial artery is used to determine the ankle–brachial index.

Appendix 3: 24-h Ambulatory Blood Pressure Monitoring

ABPM was performed in all studies according to current guidelines [12]. Each ABPM started in the morning and had to record values for at least 24 h. Measurements were performed at intervals of 15–30 min throughout the whole monitoring period. Different devices were used in the different studies. However, all of them measured BP through the oscillometric principle and were clinically validated according to current standards. In all studies, cuff sizes appropriate to study participant’s arm were used, namely standard adult cuffs for arm circumferences ranging between 24 and 32 cm and large adult cuffs for arm circumferences ranging between 32 and 42 cm. Cuffs were placed on the non-dominant arm and study participants were instructed to keep their arm still and remain motionless during the cuff’s automatic inflation. After fitting the device in the outpatient clinic, study participants were sent back to their usual activities and asked to return 24 h later to have the device unfitted and the recording terminated.