Effect of Aging on Left Atrial Compliance and Electromechanical Properties in Subjects Without Structural Heart Disease

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Effect of Aging on Left Atrial Compliance and Electromechanical Properties in Subjects Without Structural Heart Disease
Rachid Abou, MD, Melissa Leung, MBBS, BSc (Med), Anthony M. Tonsbeek, MSc, Tomaz Podlesnikar, MD, Arie C. Maan, PhD, Martin J. Schalij, MD, PhD, Nina Ajmone Marsan, MD, PhD, Victoria Delgado, MD, PhD*, and Jeroen J. Bax, MD, PhD Aging is associated with changes in left atrial (LA) structure and function.The present study aimed at describing the effect of aging on LA properties in a large cohort of subjects without structural heart disease.We divided 386 subjects (mean age 58 years [range 16 to 91]; 188 men [49%]) clinically referred for echocardiography according to age groups.The P-wave dispersion (PWD), reflecting total atrial conduction time, was measured on a 12-lead surface electrocardiogram as the difference between maximum and minimum P-wave duration.The PA-TDI duration reflecting the total atrial conduction time was measured on tissue Doppler imaging (TDI) as the time between onset of P wave on surface electrocardiogram to peak A 0 -wave velocity.Two-dimensional speckle-tracking echocardiography was used to assess LA reservoir function, reflecting LA compliance.In the overall population, mean PWD, PA-TDI, and LA reservoir strain were 43 -12 ms, 129 -27 ms, and 36 -13%, respectively.Increasing age was independently associated with prolonged PWD (b [ 0.161; p <0.001), PA-TDI (b [ 0.476; p <0.001), and reduced LA reservoir strain (b [ L0.259; <0.001), suggesting age-related fibrotic changes of the LA myocardium.The association between age and LA reservoir strain was modulated by body mass index (b [ L0.582; p <0.001) and LA volume index (b [ L0.117; p [ 0.014).In conclusion, aging is associated with longer PWD and PA-TDI duration along with a decrease in LA reservoir function.Obesity and larger LA volumes are independently associated with reduced LA compliance.Ó 2017 The Author(s).Published by Elsevier Inc.This is an open access article under the CC BY license (http://creativecommons.org/licenses/ by/4.0/).(Am J Cardiol 2017;120:140e147) Aging has been associated with structural changes of the left atrium (LA).Besides LA dilation as a marker of chronic left ventricular (LV) diastolic dysfunction, 1e3 increase in LA myocardial fibrosis has been demonstrated and associated with impaired LA function, increase in LA stiffness, and changes in LA electrophysiological properties.3e5 These structural and functional LA changes have been associated with increased risk of atrial fibrillation and heart failure. 6P-wave indexes, such as P-wave duration and P-wave dispersion (PWD), indirectly reflect the total conduction time of the LA. 7Echocardiographic tissue Doppler imaging (TDI) also permits evaluation of the total atrial conduction time (PA-TDI duration), which reflects the extent of both electrical and structural remodeling of the atria. 8Additionally, 2-dimensional (2D) speckle-tracking echocardiography enables the assessment of LA reservoir strain, a marker of LA compliance. 9PWD, PA-TDI, and LA reservoir strain may change with aging because of structural remodeling of the LA.The present study aimed at describing the effect of aging on LA properties in a cohort of subjects without structural heart disease.

Methods
A total of 386 patients who were clinically referred for cardiac evaluation and transthoracic echocardiography at the Leiden University Medical Center (The Netherlands) without structural heart disease were evaluated retrospectively. 10,11Referral reasons included evaluation of dyspnea, chest pain, screening preceding noncardiac intervention, palpitations, and evaluation of patients with high cardiovascular risk profile.Subjects with previous cardiac intervention, known history of coronary artery disease, pacemaker implantation, documented cardiac arrhythmias, LV wall motion abnormalities at rest, and any grade of valvular stenosis or more than mild valvular regurgitation were excluded.Therefore, only patients with structurally and functionally normal hearts on echocardiography and sinus rhythm on the electrocardiogram (ECG) without conduction abnormalities were included in the present evaluation.Patients were selected to obtain approximately equal proportions of gender-matched groups across 5 predetermined age categories: <45, 45 to 54, 55 to 64, 65 to 74, and >75 years.
Patient demographics and clinical data were collected.Medications including angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, b blockers, statins, diuretics, and calcium channel blockers were noted.All clinical data were stored at the departmental Cardiology Information System (EZIS chipsoft and EPD-Vision, Leiden University Medical Center).The Dutch Central Committee on Human-Related Research (CCMO) allows the use of anonymous data without previous approval of an institutional review board provided that the data are acquired for routine patient care.All data used for this study were acquired for clinical purposes and handled anonymously.
The standard 12-lead ECG was recorded at 100 mm/s paper speed and 40 mm/mV calibration.Customized software was used to analyze the PWD (Megacare Infinity VF4; Dräger Medical, Danvers, Massachusetts).PWD was defined as the time difference between maximum P-wave duration and minimum P-wave duration measured in any lead (Figure 1).The onset and end of the P wave were defined as the point of the first visible upward slope from the isoelectric line and the point of return to isoelectric line, respectively.QT interval was corrected for heart rate using the Bazett formula: QTc ¼ QT/ORÀR. 12chocardiographic data were obtained with patients at rest in the left lateral decubitus position using commercially available ultrasound systems (Vivid 7 and E9; General Electric Vingmed, Horten, Norway).Data acquisition was performed with a 3.5-MHz or M5S transducers.Standard M-mode, 2D, color, pulsed, and continuous-wave Doppler data were acquired and stored digitally for subsequent offline analysis (EchoPac BT13; GE Medical Systems, Horten, Norway).Left ventricular ejection fraction was calculated using the Simpson's biplane method. 10LV mass was calculated according to Devereux et al and indexed for body surface area. 10Diastolic function was measured according to contemporary guidelines. 13Valvular morphology and function were assessed with 2D, color, pulsed, and continuous-wave Doppler echocardiography. 11Color-coded TDI data of the LA were obtained from the apical 4-chamber view to measure the PA-TDI duration, an echocardiographic parameter representing the total atrial conduction time (a marker of electromechanical The onset and end of the P wave was defined as the point of the first visible upward slope from the isoelectric line and the point of return to isoelectric line.P-wave dispersion is defined as the difference between P-maximum duration and P-minimum duration. Miscellaneous/Age-Related LA Remodeling delayereflecting atrial fibrosis).To assess the PA-TDI duration, a fixed 9 Â 9 pixel region of interest was placed on the LA lateral wall just above the mitral annulus to obtain the time velocity tracing of the LA wall.The time interval between the onset of the P wave in lead II of the surface ECG and the peak A 0 -e on TDI defined the PA-TDI (Figure 2). 8A reservoir strain was evaluated using 2D speckle tracking on the apical 4-chamber view.The ECG was referenced to the onset of the QRS complex or the Q wave, and the region of interest was adjusted to the LA wall thickness.LA reservoir strain was measured as the peak longitudinal strain during ventricular systole (Figure 3). 14ontinuous variables are reported as mean AE SD.Oneway ANOVA was used to compare continuous variables across the groups.Categorical variables are reported as frequencies and percentages and were analyzed using the chi-square test.Pairwise comparisons were performed to assess differences across age categories.Univariate and multivariate linear regression analyses were performed to identify clinical, ECG, and echocardiographic correlates of LA functional characteristics (PWD, PA-TDI, and LA reservoir function).The level of significance for univariate analysis was set at p <0.20.Statistical analysis was performed on SPSS for Windows, v20.0 (IBM, Armonk, New York).A 2-tailed p value <0.05 was considered statistically significant.

Results
Mean age of the patients was 58 years (range 16 to 91) and 188 (49%) were men.The clinical characteristics of the patients divided according to the 5 pre-determined age categories are presented in Table 1.A total of 365 patients (95%) had analyzable 12-lead surface ECGs (Table 2).The mean PWD was 43 AE 12 ms for the overall population.A significant increase in the duration of PWD across age categories was observed (p <0.001).In contrast, there was no significant difference in the average P wave (p ¼ 0.100).Echocardiographic characteristics across the age groups are presented in Table 3. PA-TDI duration analysis was feasible in all patients.The mean PA-TDI duration was 129 AE 27 ms in the overall population.PA-TDI duration significantly increased with aging (Table 3).Analysis of LA reservoir strain was feasible in all patients.The mean LA reservoir strain was 36 AE 13% in the overall population.When analyzing the age categories, LA reservoir strain significantly decreased with aging (Table 3).These findings indicate that aging was associated with slow LA conduction and reduced LA compliance, suggesting the presence of increasing fibrosis of the LA wall.

Discussion
The present study reports the values of PWD, PA-TDI, and LA reservoir strain across a wide age range in a large group of subjects without structural heart disease.With increasing age, the LA conduction becomes slower and the LA compliance reduces, suggesting the presence of agerelated fibrotic changes of the LA wall.In addition, larger body mass index and LA volume index were independently associated with reduced LA reservoir strain.
Aging is related to structural remodeling of the LA myocardium.3e5 This structural remodeling may become pathologic and form the substrate for the occurrence of atrial fibrillation or lead to heart failure. 6,15Differentiation between physiological and pathologic LA structural remodeling is challenging.Current noninvasive imaging techniques permit evaluation of LA dimensions and geometry and LA myocardial tissue characterization.Dilated LA and the presence of macroscopic fibrosis on magnetic resonance  Data are presented as mean AE standard deviation or as number (percentage).Hypertension was defined as blood pressure !140/90 mm Hg or using anti-hypertensive therapy.Hypercholesterolemia was defined as total cholesterol 190 mg/dl or using lipid-lowering medication.Diabetes mellitus was defined as fasting blood glucose !7.0 mmol/L, 2-h oral glucose tolerance test glucose !11.1 mmol/L or using anti-diabetic medication.
Miscellaneous/Age-Related LA Remodeling imaging are the hallmark of LA structural remodeling. 16owever, dilation of the LA is rather unspecific and not always pathologic (e.g., in endurance athletes) and detection of macroscopic fibrosis with late gadolinium contrastenhanced magnetic resonance requires high expertise in image acquisition and postprocessing and its availability remains low.The present study proposed 3 parameters that characterize the LA structural remodeling combining electromechanical properties of the LA wall and evaluated the age-related changes of these parameters and their correlates.The increased collagen deposition and myocardial fibrosis of the LA myocardium associated with aging lead to slow conduction of the action potential which is reflected by prolongation of the PWD on ECG and PA-TDI duration on echocardiography.In addition, this increased myocardial fibrosis may result in reduced LA compliance which is reflected by reduced LA reservoir strain on echocardiography.
There is accumulating evidence concerning the potential role of PWD, PA-TDI, and LA reservoir strain for risk stratification of patients with various cardiovascular pathologies.However, reference values indicating normal LA physiological properties have not been well established.Data from the Framingham Heart Study including 295 patients (age range between 25 and 85 years, 52% men) showed a median PWD of 34 ms (interquartile range 28 to 43 ms). 17In addition, a recent meta-analysis including 80 studies with a total of 6,827 healthy participants aged between 25 and 45 years reported a weighted mean value of PWD of 33.46 AE 9.65 ms. 18The present study reports slightly longer PWD values (43 AE 12 ms) than previous studies, 17,18 but this may be related to a larger proportion of subjects aged >75 years (17%) in the present study (13% in the Framingham Heart Study while the meta-analysis included age categories up to 45 years of age). 18everal studies have shown the age dependency of PA-TDI duration. 19,20Erdem et al 19   Miscellaneous/Age-Related LA Remodeling p ¼ 0.001).Weijs et al 20 evaluated the correlates of PA-TDI in 427 patients and reported a mean PA-TDI duration of 157 AE 22 ms, whereas age was independently associated with increasing PA-TDI on multivariable analysis (each 10-year increase in age was associated with 5 ms increase in PA-TDI).However, that study included a broad spectrum of patients (with history of atrial fibrillation, heart failure, and valvular heart disease), and therefore, the PA-TDI values do reflect more than just the effect of aging.
Finally, the association between aging and changes in LA reservoir strain has been demonstrated in previous studies. 3,5,21,22In 188 healthy subjects (21 to 80 years; 43% male) free of cardiovascular disease or cardiovascular risk factors, Boyd et al 21 showed that TDI-derived global longitudinal strain of the LA (representing reservoir function) was independently associated with age.Interestingly, the reduction in LA reservoir strain was apparent from the sixth decade, whereas LA dilation was observed from the seventh decade, suggesting that LA strain measures may be more sensitive of structural LA changes than conventional echocardiographic parameters.In the present study, there were no significant changes in LA volume and LV mass.However, we did observe a higher prevalence of diastolic dysfunction with increasing age.The association between age and LA reservoir strain was modulated by LA volume, suggesting that diastolic dysfunction leads to dilation of the LA, and therefore, the influence of age on LA reservoir strain is reduced.In addition, the present study demonstrated that LA reservoir strain is independently associated with BMI.In overweight and obese patients, it has been demonstrated that the increase of epicardial fat tissue is associated with increased LA dimensions and reduced LA compliance. 23n 70 patients (including 50% obese patients, with BMI !30 kg/m 2 ), Erdem et al 24 showed that LA reservoir strain was significantly more reduced in obese patients compared with their counterparts (33.1 AE 8.8% vs 46.2 AE 8.9%, p <0.001, respectively).
Several limitations should be acknowledged.The present study was retrospective in nature and did not include "healthy" subjects because a significant proportion had cardiovascular risk factors or used cardiovascular medication that may influence LA mechanics.However, after correction for these confounding factors, there were strong associations between age and electromechanical properties of the LA.The clinical implications of these findings remain unknown and future studies are needed to demonstrate whether therapy (control of risk factors) may modulate the age-related changes in the electromechanical properties of the LA.Furthermore, a longitudinal design of the study would have allowed for evaluation of changes in LA electromechanical properties according to changes in loading conditions.In addition, late gadolinium contrast-enhanced cardiac magnetic resonance was not performed to demonstrate the presence of LA fibrosis and correlate it with the electromechanical LA properties.Finally, LA strain measurements were performed with dedicated post-processing software, and the values obtained with this software may not be generalized to other vendors.

Disclosures
The Department of Cardiology of the Leiden University Medical Center received grants from Biotronik, Medtronic, Boston Scientific Corporation, and Edwards Lifesciences.Dr. Delgado received speaker fees from Abbott Vascular.

Figure 1 .
Figure 1.P-wave dispersion measured on 12-lead ECG.Panel A shows a full cardiac cycle in lead I obtained from a standard 12-lead ECG.Panel B is an enlargement of the box plotted in section A which indicates the maximum P-wave duration.Panel C shows 1 full cardiac cycle in lead V1 obtained from a standard 12-lead ECG.Panel D shows a zoomed view of the box in section C which indicates the minimal the P-wave duration.The onset and end of the P wave was defined as the point of the first visible upward slope from the isoelectric line and the point of return to isoelectric line.P-wave dispersion is defined as the difference between P-maximum duration and P-minimum duration.

Figure 2 .
Figure 2. PA-TDI duration by TDI with 2D echocardiography.On bidimensional and TDI image of the apical 4-chamber view, the region of interest is placed in the LA lateral wall above the mitral annulus.This region of interest tracks the movement of the myocardium along the cardiac cycle and the velocity of the myocardium is plotted in the time-velocity curve.The PA-TDI duration is assessed by measuring the time interval between the onset of the P wave in lead II of the surface ECG and the peak A 0 wave on the tissue Doppler tracing.

Figure 3 .
Figure 3. Left atrial speckle tracking with 2D echocardiography.The LA endocardium is manually traced in the apical 4-chamber view, and the region of interest is adjusted to fit the thickness of the LA wall.Strain curves for individual segments are illustrated.LA reservoir strain is measured as the peak global longitudinal strain during ventricular systole, which is indicated by the dotted line within the strain curves.
demonstrated in 80 healthy subjects aged between 20 and 40 years that the PA-TDI duration increased with older age (b ¼ 0.342,

Table 1
Clinical characteristics divided by age categories

Table 2
Electrocardiographic characteristics divided by age categories Data are presented as mean AE standard deviation.bpm ¼ beats per minute; LA ¼ left atrial; LV ¼ left ventricular; TDI ¼ tissue Doppler imaging.

Table 5
Univariate and multivariate linear regression analyses to evaluate correlates of left atrial conduction time on tissue Doppler imaging (PA-TDI)

Table 6
Univariate and multivariate linear regression analyses to assess correlates of left atrial reservoir function ACEi ¼ angiotensin converting enzyme inhibitor; ARB ¼ angiotensin II receptor blocker; BMI ¼ body mass index; CI ¼ cinfidence interval; LA ¼ left atrial; LV ¼ left ventricular; TDI ¼ tissue Doppler imaging.