Methods
Study Population
Data were acquired from a population-based survey of heart failure which enrolled the entire community-dwelling older population of Dicomano, a small town near Florence, Italy (‘Insufficienza Cardiaca negli Anziani Residenti a Dicomano’, ICARe Dicomano Study). The general design of this survey has been previously published in detail (1). All community-dwelling individuals aged 65 years recorded in the City Registry Office were eligible for an extensive geriatric assessment consisting of home interview, laboratory testing and clinical examination. Proxy interviews were obtained in 29 cases with severe cognitive and/or sensory impairment. Further clinical information was gathered from participants’ primary care physicians, who answered a structured questionnaire regarding the history and treatment of several clinical conditions, including hypertension. The presence and severity of comorbid conditions (dyslipidemia, stroke, transient ischemic attack, coronary artery disease, peripheral vascular disease, and diabetes) were established using diagnostic algorithms based on medical history, laboratory and other diagnostic tests, and physical findings (1).
Blood pressure measurement and diagnosis of hypertension
Blood pressure (BP) was measured by the study physician, with the participant in the supine position for a 10-minute rest period, using a cuff sized for arm circumference. A first measure was taken in each arm. Two further readings were obtained 1-2 minutes apart, usually in the dominant arm, except when SBP differed between the two sides by more than 10 mmHg. In these cases, the side with the highest SBP was chosen. DBP was defined as the disappearance of the fifth Korotkoff sound. The second and the third BP measurements were averaged, and mean values were considered as the reference SBP and DBP.
Subjects receiving antihypertensive medication were excluded from the present study. Enrolled subjects were grouped according to the following criteria: HTN = DBP 90 mmHg; borderline ISH = SBP 140-159 mmHg and DBP <90 mmHg, and ISH = SBP 160 mmHg and DBP <90 mmHg. Subjects with BP <140/90 mmHg were considered normotensive; their data were previously published (2).
One hundred seventy three subjects were normotensive while 438 subjects were hypertensive (3) (72% of the 611 subjects included in the study): 265 subjects had HTN, 106 had borderline ISH and 67 had ISH. One hundred seventy (65%) HTN, 19 (18%) borderline ISH and 24 (14%) ISH subjects were taking antihypertensive medication, resulting in 95 unmedicated subjects in the HTN group, 87 in the borderline ISH group, and 43 in the ISH group. Previously-treated hypertensive subjects were off medications for at least 1 month.
Echocardiography
Two-dimensionally-targeted M-mode echocardiograms were recorded with the subject in a partial left decubitus position. M-mode recordings were performed with the ultrasound beam at or just below the tips of the mitral valve leaflets. Septal and posterior wall thickness and left ventricular (LV) chamber dimensions were measured according to the American Society of Echocardiography (ASE) convention(4). If the M-mode cursor could not be properly aligned along the LV minor axis, linear measurements of LV wall thicknesses and internal dimensions were made from two-dimensional parasternal long-axis recordings according to the recommendations of the ASE (5). LV diastolic filling parameters were derived from the pulsed-wave Doppler mitral inflow pattern recorded with the sample volume placed between the tips of the mitral valve leaflets in the apical 4-chamber view (6). M-mode, two-dimensional, and Doppler images were recorded on 0.5-inch videotape and subsequently read by an operator in a blinded manner using a review unit (TomTec P90); values were averaged from up to 6 cardiac cycles. LV mass was calculated as:
1
where IVSd and PWTd are the diastolic thicknesses of the interventricular septum and LV posterior wall, respectively, and LVIDd is the diastolic LV internal diameter. Subjects were considered to have normal LV mass if LV mass/body surface area was 116 g/m2 in men and 104 m/g2 in women (7). Subjects were classified as having significant valvular disease if severe stenosis and/or insufficiency was detected by Doppler echocardiography. Of the 225 untreated subjects included in the present study, 222 (98.7%) underwent echocardiographic examination.
Carotid Ultrasonography
As previously described (8,9), imaging of both carotid arteries was performed using a commercially-available ultrasound system equipped with a 7.5 MHz imaging transducer (SIM 5000, ESAOTE Biomedica). With the subject in the supine position and the neck in slight hyperextension, the common carotid artery, carotid bulb, and the extracranial portions of internal and external carotid arteries were identified. Two-dimensionally guided M-mode tracings of the distal left common carotid artery (about 1 cm proximal to the carotid bulb) were obtained with simultaneous ECG and contralateral carotid pressure waveform tracings (see below) and were recorded on 0.5-inch videotape. After the videotape was reviewed, frames suitable for measurement of M-mode images were obtained using a frame grabber (Imaging Technology Inc.) interfaced with a high-resolution (768x576 pixels) video monitor and stored on diskette.
Carotid measurements were performed on the stored images using mouse-driven software written by one of the investigators (ARTSS©: Arterial Structure and Stiffness; Copyright Cornell Research Foundation), after calibration for depth and time. The simultaneous carotid pressure tracing (see below) was used to time the carotid artery measurement at end diastole (minimum arterial pressure) and at the time of peak-systolic pressure. Measurements included the combined intimal-medial thickness (IMT) of the far wall at end diastole, as validated in anatomic correlation studies (10), and end-diastolic and peak-systolic internal dimensions obtained by continuous tracing of the intima-lumen interface of the near and far walls. All measurements were performed on several cycles and averaged. Carotid ultrasound examination and carotid pulse recording were obtained in 224 (99.6%) of the patients included in this analysis.
Relative wall thickness (RWT) of the common carotid artery was calculated according to the formula:
where Dd is the diastolic carotid diameter. Because increased distending pressure, as occurs in hypertensive patients, could decrease the IMT due to vessel wall stretching, carotid intimal-medial cross-sectional area (CSA) was also calculated as an estimate of circumferential intimal-medial tissue mass (11,12).
Both carotid arteries were scanned using two-dimensional imaging to identify the presence and size of atherosclerotic plaques, defined as focal increases in IMT >50% of the surrounding wall; standard wall thickness measurements were never obtained at the level of a discrete plaque. Plaque number was defined as the number of discrete plaques within both right and left carotid arteries. Plaque thickness was measured in the projection that showed maximal encroachment into the vessel lumen.
Carotid Artery Stiffness
As previously described (13), simultaneous carotid pressure waveforms were obtained (14,15) using a high-fidelity external pressure transducer (Millar Instruments, Inc.) applied to the skin overlying the pulse of the contralateral common carotid artery. The transducer is internally calibrated (0.2 V/100 mmHg) and registers absolute changes in applied pressure over a range of 300 mmHg. To obtain carotid blood pressure values, the waveforms require additional external calibration. Based on the observation that mean and diastolic pressures were nearly identical in all arterial capacitance vessels (16-18), brachial artery pressure was measured by the cuff and mercury sphygmomanometer method with the patient in the supine position, and mean pressure (MBP) was calculated as:
The resultant value was assigned to the planimetrically computer-derived mean blood pressure of the carotid waveforms and the diastolic brachial pressure was assigned to the diastolic carotid pressure. Carotid artery stiffness was calculated by the pressure-independent stiffness index , which takes into account the logarithmic relation between arterial pressure and diameter (19,20).
The systolic portion of the carotid waveform was analyzed to calculate the augmentation index (AI) (21,22), a means of quantifying the contribution of reflected pressure waves to the central pulse pressure (PP). After identification of the early and late systolic peaks and the inflection that separates them, pressures were determined at peak systolic pressure (Ppk) and at the inflection point (Pi) by using the previously-described calibrated computer system. The amplitude of the reflected wave was calculated as the difference Ppk-Pi (when Ppk occurred in late systole) or as Pi-Ppk (when Ppk occurred in early systole). As proposed by Murgo et al. (22), the amplitude of the reflected wave was divided by the PP. In view of the fact that the contribution of the reflected wave might be somewhat attenuated by the larger PP found in the ISH patients, a modified AI was calculated dividing the amplitude of the reflected wave by the mean BP. Measurements were averaged from several cycles.
Statistical Analysis
Data are expressed as meanSD. Differences between three groups were tested by one-way analysis of variance and Scheffé post-hoc test for continuous variables.ANCOVA with Sidak’s post-hoc test was also performed to compare groups after controlling for age, PP and SPB. Differences between groups were tested by 2 statistics for proportions and Bonferroni correction for multiple comparisons. Relations between continuous variables were evaluated by linear regression analysis. Variables that were found to be significant in univariate analyses were considered as potentially independent variables in multiple linear regression analysis. Two-tailed p<0.05 was considered significant.
References
1. Di Bari M, Marchionni N, Ferrucci L, Pini R, Antonini E, Chiarlone M, Marsilii A, De Alfieri W, Fumagalli S, Masotti G. Heart failure in community-dwelling older persons: aims, design and adherence rate of the ICARe Dicomano project: an epidemiologic study. Insufficienza Cardiaca negli Anziani Residenti a Dicomano. J Am Geriatr Soc. 1999;47:664-671.
2. Pini R, Cavallini MC, Bencini F, Silvestrini G, Tonon E, Marchionni N, Di Bari M, Devereux RB, Masotti G, Roman MJ. Cardiac and vascular remodeling in older adults with isolated systolic hypertension: the ICARe Dicomano study. Circulation. 2000;102 (Suppl II):II-698. Abstract.
3. Di Bari M, Salti F, Nardi M, Pahor M, De Fusco C, Tonon E, Ungar A, Pini R, Masotti G, Marchionni N. Undertreatment of hypertension in community-dwelling older adults: a drug-utilization study in Dicomano, Italy. J Hypertens. 1999;17:1633-1640.
4. Sahn D, DeMaria A, Kisslo J, Weyman A, for the Committee on M-mode Standardization of the American Society of Echocardiography. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978;58:1072-1083.
5. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux RB, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, Silverman NH, Taijk AJ. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2:358-367.
6. Appleton CP, Jensen JL, Hatle LK, Oh JK. Doppler evaluation of left and right ventricular diastolic function: a technical guide for obtaining optimal flow velocity recordings. J Am Soc Echocardiogr. 1997;10:271-292.
7. Palmieri V, Dahlof B, DeQuattro V, Sharpe N, Bella JN, de Simone G, Paranicas M, Fishman D, Devereux RB. Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. J Am Coll Cardiol. 1999;34:1625-1632.
8. Roman MJ, Pickering TG, Schwartz JE, Pini R, Devereux RB. Association of carotid atherosclerosis and left ventricular hypertrophy. J Am Coll Cardiol. 1995;25:83-90.
9. Roman MJ, Saba PS, Pini R, Spitzer M, Pickering TG, Rosen S, Alderman MH, Devereux RB. Parallel cardiac and vascular adaptation in hypertension. Circulation. 1992;86:1909-1918.
10. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation. 1986;74:1399-1406.
11. Lemne C, Jogestrand T, de Faire U. Carotid intima-media thickness and plaque in borderline hypertension. Stroke. 1995;26:34-39.
12. Roman MJ, Pickering TG, Pini R, Schwartz JE, Devereux RB. Prevalence and determinants of cardiac and vascular hypertrophy in hypertension. Hypertension. 1995;26:369-373.
13. Roman MJ, Pini R, Pickering TG, Devereux RB. Non-invasive measurements of arterial compliance in hypertensive compared with normotensive adults. J Hypertens. 1992;10:S115-S118.
14. Saba PS, Roman MJ, Pini R, Spitzer M, Ganau A, Devereux RB. Relation of arterial pressure waveform to left ventricular and carotid anatomy in normotensive subjects. J Am Coll Cardiol. 1993;22:1873-1880.
15. Saba PS, Cavallini MC, Scorzoni D, Longhini C, Pini R, Ganau A. Arterial tonometry: principles and clinical applications in hypertension. High Blood Press. 1996;5:241-250.
16. Hamilton WF, Dow P. An experimental study of the standing waves in the pulse propagated through the aorta. Am J Physiol. 1939;123:48-59.
17. Schnabel TG, Jr., Fitzpatrick HF, Peterson LH, Rashkind WJ, Talley D, Raphael RL. A technic of vascular catheterization with small plastic catheters. Its utilization to measure the arterial pulse wave velocity in man. Circulation. 1952;5:257-262.
18. Kroeker EJ, Wood EH. Comparison of simultaneously recorded central and peripheral aretrial pressure pulses during rest, exercise and tilted position in man. Circ Res. 1955;3:623-632.
19. Kawasaki T, Sasayama S, Yagi S, Asakawa T, Hirai T. Non-invasive assessment of the age related changes in stiffness of major branches of the human arteries. Cardiovasc Res. 1987;21:678-687.
20. Hirai T, Sasayama S, Kawasaki T, Yagi S. Stiffness of systemic arteries in patients with myocardial infarction. Circulation. 1989;80:78-86.
21. Kelly R, Daley J, Avolio A, O'Rourke M. Arterial dilation and reduced wave reflection. Benefit of dilevalol in hypertension. Hypertension. 1989;14:14-21.
22. Murgo JP, Westerhof N, Giolma JP, Altobelli SA. Aortic input impedance in normal man: relationship to pressure wave forms. Circulation. 1980;62:105-116.
1