The aim of this study was to investigate the relationship between carotid artery stiffness and diastolic function in a cohort of subjects without known cardiovascular risk factors and/or overt cardiovascular disease.
Ninety-two healthy subjects underwent transthoracic echocardiographic Doppler and carotid echo-tracking studies. Measurements of local arterial stiffness were obtained at left common carotid artery level; stiffness parameter (β), and pressure-strain elasticity modulus (Ep) were calculated as well as intima-media thickness (IMT).
Stiffness parameter and Ep were correlated inversely with transmitral E wave ( P < .01), E/A ratio, and septal Em ( P < .01) and positively with A wave ( P < .001). IMT was also associated with A wave, E/A ratio, Em, and Am but not with E wave. No association was found between IMT, β, and Ep. The correlation between arterial stiffness and left ventricular diastolic function remained significant after multivariate adjustment for age, sex, pulse pressure, and body mass index, but not with IMT.
In healthy subjects, changes in central carotid stiffness are in line with left ventricular diastolic function independently of age, sex, pulse pressure, and body mass index.
It is well known that arterial stiffness is a primary and strong independent predictor of cardiovascular morbidity and mortality and is associated with multiple cardiovascular risk factors—including hypertension, dyslipidemia, obesity, smoking, diabetes, and aging—all of which also favor the development of atherosclerosis. Recently, the European guidelines for the diagnosis and treatment of hypertension recommended the assessment of arterial stiffness as evidence of target organ damage. It seems logical that impaired arterial compliance would be associated with ventricular dysfunction via atherosclerosis. Arterial stiffness is correlated with the presence and severity of atherosclerosis, and subclinical atherosclerosis is also associated with myocardial dysfunction. Although the relationship between arterial stiffness and left ventricular (LV) diastolic function has been previously reported, data in subjects without known cardiovascular disease and/or risk factors are limited. In the present study, we examined the hypothesis of a relationship between LV diastolic function and carotid arterial stiffness among healthy subjects as assessed by tissue Doppler echo tracking.
Ninety-two consecutive Caucasian volunteers without known cardiovascular risk factors and/or overt cardiovascular disease (58 men, 34 women; mean age, 46.0 ± 13.3 years) were enrolled. The study population, referred to the local hospital, had undergone voluntary screening for cardiovascular disease at our outpatient clinic, which included a questionnaire about medical history, the use of drugs in the previous 5 years, cardiovascular risk factors, and lifestyle habits (alcohol intake, smoking, and physical activity). The questionnaire was completed with data from hospital charts and/or personal records when available. None of the subjects were taking drugs chronically, and the clinical histories of these healthy volunteers were uneventful. To generate a healthy sample, participants were excluded for the following reasons: hypertension (systolic blood pressure [BP] ≥ 140 mm Hg and diastolic BP ≥ 90 mm Hg confirmed by home BP measurements or drug treatment for hypertension), diabetes (treatment with insulin or an oral hyperglycemic agent), treatment for dyslipidemia, and history of cardiovascular disease (coronary artery disease, congestive heart failure, stroke, transient ischemic attack or intermittent claudication).
Oscillometric BP and heart rate measurements were taken twice in the right arm after 10 min in the supine position in a quiet room using a mercury sphygmomanometer, just before the transthoracic echocardiographic exam and once before the carotid study was begun (≥30 min after the first measurement). Phase V Korotkoff sounds were considered as diastolic BP except in subjects with sounds tending toward zero, in whom phase IV was taken. For the calculation of the carotid stiffness parameters, the BP taken before the carotid exam was entered into the program. The BP measurements taken before echocardiography were considered for the calculation of pulse pressure [PP] (systolic BP − diastolic BP). Weight (in kilograms) and height (in meters) were measured using standard techniques, and body mass index (BMI) was calculated as body weight divided by height squared. Body surface area was calculated using the DuBois formula (0.20247 × height 0.725 × weight 0.425 ).
The study was approved by the institutional ethics board, and informed consent was obtained from the participants.
Standardized transthoracic and Doppler echocardiographic examinations were performed using commercially available equipment in all subjects (Alpha 10; Aloka, Tokyo, Japan) in accordance with the American Society of Echocardiography’s guidelines under continuous electrocardiographic recording. Specific views included the parasternal long-axis and short-axis views (at the mitral valve and papillary muscle levels) and apical four-chamber, two-chamber, and three-chamber views. Pulsed-wave and continuous-wave Doppler interrogation was performed on all four cardiac valves. All studies were reviewed and analyzed offline by two independent observers blinded to the clinical characteristics of the study population. Each parameter was assessed in three to five consecutive cardiac cycles, and the mean values were obtained for the purposes of our study.
M-Mode and B-Mode Measurements
M-mode measurements (LV diastolic and systolic diameters, interventricular septal and posterior wall thickness) were performed in the parasternal short-axis view, two-dimensionally guided, with the patient in the left lateral position. LV mass was calculated using the Penn convention as 1.04[(interventricular septal thickness in diastole + LV internal diameter in diastole + posterior wall thickness in diastole) 3 − (LV internal diameter in diastole) 3 ] − 13.6 and was indexed for body surface area. Relative diastolic wall thickness was determined as (interventricular septal thickness in diastole + posterior wall thickness in diastole)/LV internal diameter in diastole. LV ejection fraction was calculated using Simpson’s rule in the apical four-chamber view. Left atrial maximal volume was measured at the point of mitral valve opening using the biplane area-length method and corrected for body surface area.
Color Doppler Analysis
Valvular regurgitation was quantified from color Doppler imaging and categorized as absent, minimal (within normal limits), mild, moderate, or severe.
Doppler-derived LV diastolic inflow was recorded in the apical four-chamber view by placing the sample volume at the level of the tips. The following LV diastolic variables were measured: E and A peak velocities (in meters per second) and their ratio and E-wave deceleration time (the time elapsed between peak E velocity and the point at which the extrapolated deceleration slope of the E velocity crosses the zero baseline). Pulse Doppler tissue imaging (DTI) was carried out in the four-chamber view at the septal mitral annular level. The peak velocity of myocardial systolic wave (Sm), early peak (Em) and atrial (Am) diastolic wave (in centimeters per second), and the E/Em ratio were recorded.
To test the reliability of DTI measurements according to recent guidelines, an additional group of 53 subjects with the same characteristics as the subjects of the original study (mean age, 44.5± 15.9 years; 39 men) were prospectively studied, using average values of septal and lateral mitral annular measurements.
Carotid Artery Stiffness Parameters
Measurements of local arterial stiffness were obtained at the level of the left common carotid artery 1 to 2 cm below the bifurcation (using a high-definition echo-tracking system implemented in the Alpha 10). The examination was performed immediately at the end of the echocardiographic study using a 7.5-MHz linear probe. Echo-tracking uses the raw radiofrequency signals that are based on the video signals. For measurements of diameter change by echo tracking, the optimal angle between the ultrasound beam and the vessel wall is 90°. However, if the blood flow is perpendicular to the beam, it is not detected. To overcome this problem, a different ultrasound beam for measurements of diameter change and blood velocity was used, and blood velocity measurements were independently steerable. Figure 1 shows a long-axis view of the common carotid artery and the ultrasound beam configuration with the independent beam steering function. The solid line shows the ultrasound beam direction for velocity measurements, while the dotted line shows the beam direction for measurements of diameter change. These beams were steered to intersect at the center of the range gate. The steering angle of each ultrasound beam can be changed in 5° increments from −30° to +30°. The echo-tracking gates are manually set at the boundaries between the intima and media of the anterior and posterior walls. The rate gate for velocity measurements was automatically positioned at the center of the diameter using echo-tracking gates. Flow velocity is corrected for the angle between ultrasound beam direction and flow velocity vector. The right section of Figure 1 represents the M-mode for the carotid diameter measurements. During systole, the pressure and diameter change waveforms were very similar. During diastole, the carotid arterial pressure-diameter relationship showed slight nonlinearity and hysteresis. The maximal and minimal values of a diameter change waveform were calibrated according to the systolic and diastolic relationship. The relationship of pressure to diameter is thought to be linear. Brachial cuff BP was measured just before starting the carotid study and was entered into the system for the calculation of carotid stiffness parameters. Three to five beats were averaged to obtain a representative waveform.
The following indices were automatically calculated: β index, ln[(Ps/Pd)/(Ds − Dd)/Dd)], Ep (pressure-strain elasticity modulus), and (Ps − Pd)/(Ds − Dd)/Dd ( Figure 2 ), where Ps is systolic BP, Pd is diastolic BP, Ds is arterial systolic diameter, and Dd is arterial diastolic diameter.
Intima-Media Thickness (IMT) Measurement
In 76 subjects from the original cohort of 92 normal subjects, IMT was measured at the far wall of the left common carotid artery 10 to 15 mm proximal to the carotid bulb by an investigator who was blinded to measures of carotid stiffness.
An additional group of 53 subjects with the same clinical characteristics as the subjects of the original cohort were studied. They underwent echocardiography and arterial stiffness and IMT determination. In this group, DTI measurements were done at the septal and lateral mitral annulus, and the mean between the two was considered.
Data are presented as mean ± SD for variables with normal distribution and as median (interquartile range) for skewed variables. The Shapiro-Wilk test ( P < .05 for rejecting the null hypothesis) was used to test the normality of the distribution. We used Pearson’s correlation analysis to assess univariate correlations between arterial stiffness parameters, IMT, and LV structure and functional variables. Pearson’s correlation was also used to evaluate whether age, PP, sex, and BMI were associated with arterial stiffness, systolic and diastolic function, and LV structure. Covariate analysis was then applied to adjust first for the effect of age and second for the effects of age, PP, sex, and BMI combined. The level of statistical significance was set at .05. Data analysis was performed using Stata version 10.0 (StataCorp LP, College Station, TX).
Study population characteristics, echocardiographic parameters, and arterial stiffness variables are shown in Table 1 .
|Variable||Total population |
( n = 92)
( n = 34)
( n = 58)
|Age (y)||46 ± 13.3||47.8 ± 14.7||45 ± 12.5|
|Weight (kg)||73.5 ± 12.7||62.2 ± 8.6||80.2 ± 9.7|
|Waist (cm)||89.4 ± 11.5||81.6 ± 10.2||94.2 ± 9.5|
|BMI (kg/m 2 )||24.75 ± 3.4||22.3 (20.7–24.5)||25.26 (23.8–27.5)|
|Office systolic BP (mm Hg)||129.8 ± 16.0||127.5 ± 13.4||131.2 ± 17.3|
|Office diastolic BP (mm Hg)||79.4 ± 10.0||77.7 ± 9.6||80.4 ± 10.2|
|PP (mm Hg)||50 (44–54)||50 (44–54)||50 (45–56)|
|HR (beats/min)||71.1 ± 10.7||73.7 ± 8.6||68.1 ± 11.3|
|LVIDD (mm)||50.7 ± 5.2||47.5 ± 4.6||52.7 ± 4.6|
|IVSD (mm)||8 (7–9)||7 (7–8)||8 (8–10)|
|PWTD (mm)||8 (7–9)||7 (7–8)||9 (8–10)|
|EF (%)||61.8 ± 5.8||61.44 ± 5.7||62.0 ± 5.9|
|Doppler Transmitral flow|
|E (m/sec)||0.68 ± 0.1||0.69 (0.61–0.81)||0.66 ± 0.2|
|A (m/sec)||0.51 ± 0.2||0.55 ± 0.2||0.46 (0.37–0.56)|
|E/A ratio||1.55 ± 1.2||1.72 ± 1.8||1.46 ± 0.5|
|Deceleration time (msec)||246 (198–289)||233.90 ± 69.5||252.5 (198–289)|
|Sm (m/sec)||0.09 (0.08–0.1)||0.09 (0.08–0.1)||0.09 (0.08–0.1)|
|Em (m/sec)||0.11 (0.09–0.12)||0.114 ± 0.03||0.10 ± 0.03|
|Am (m/sec)||0.11 (0.09–0.12)||0.11 ± 0.02||0.1 (0.09–0.12)|
|E/Em ratio||6.43 ± 1.6||6.24 ± 1.3||6.54 ± 1.8|
|β||5.5 (4.4–6.8)||5.9 (4.5–7.5)||5.3 (4.3–6.7)|
|Ep (kPa)||77 (58–98)||77.5 (60–96)||77 (56–98)|
|IMT (mm)||0.696 ± 0.117||0.689 ± 0.12||0.706 ± 0.116|
Correlations between β and Ep and diastolic function indices are presented in Table 2 . The correlations were negative with E and Em waves and E/A ratio and positive with the late portion of diastolic function (A wave) and deceleration time. Am and E/Em ratio were not correlated with β and Ep. IMT was also associated with A wave, E/A ratio, Em, and Am but not with E wave ( Table 2 ). As expected, age was correlated significantly with arterial stiffness and diastolic functional variables ( Table 3 ). The same pattern of correlation was found between arterial stiffness parameters and PP and BMI ( Table 3 ). IMT was associated with age, but no relations were found with BMI and PP ( Table 3 ). No associations were found between IMT and β ( r = 0.16, P = .10) and Ep ( r = 0.3, P = .088).
|Parameter||E wave||A wave||E/A ratio||Deceleration time||Em||Am||E/Em|
|β||Ep||IMT||E wave||A wave||E/A ratio||Deceleration time||Em||Am|