Abstract
Background
Advanced age is related with left ventricular (LV) remodeling. We sought to investigate the relationships between aging, elevated hemodynamic load, cardiac mechanics and LV remodeling in an elderly community-based population.
Methods and Results
We studied 1,105 subjects (76±5 years, 61% women) without prevalent heart failure, who attended the visit 5 of the Atherosclerosis Risk in Communities (ARIC) Study. Left ventricular global longitudinal (GLS), circumferential (GCS) strain and torsion indices were analyzed using three-dimensional echocardiography (3DE). Advanced age was associated with greater LV concentricity, lower myocardial diastolic relaxation, reduced GLS (adjusted estimate: 0.39±0.19% (SE)/decade, p=0.038), borderline greater GCS (adjusted estimate: −0.59±0.36% (SE)/decade, p=0.08), and higher torsion indices (adjusted estimate for torsion: 0.33±0.04° (SE)/decade, p<0.001). In addition, greater concentricity was associated with decreased GLS and greater torsion in multivariable models (all p<0.001). Women showed smaller LV cavity size, greater concentricity, lower myocardial relaxation velocity E′, though demonstrated greater GLS, GCS, and torsion than men (all p<0.05). Overall, subjects with hypertension and increasing age were more likely to have higher torsion, though the association between advanced age and greater torsion were more pronounced in women than in men (both interaction p<0.05).
Conclusions
In an asymptomatic, senescent community-dwelling population, we observed a distinct, sex-specific pattern of cardiac remodeling. While we observed worse diastolic and longitudinal function with advanced age or elevated load in both genders, a significant increase of torsion was more pronounced in women.
Keywords: elderly, longitudinal strain, circumferential strain, torsion, three-dimensional (3D) echocardiography
Alterations in left ventricular structure, or remodeling, are recognized to contribute to the development of heart failure (HF)1. LV remodeling may be intrinsically related to the senescence process and in part driven by age-related co-morbidities, such as elevated hemodynamic load due to longstanding hypertension and vascular stiffness,1,2 that lead to initially asymptomatic alterations in diastolic function and longitudinal systolic function. 2,3,4,5 It has been postulated that myocardial twist may increase as a response to the loss of longitudinal function that occurs with aging, and that this compensation may help preserve ejection fraction. Furthermore, these alterations have been noted to be different between men and women, as a greater degree of cardiac torsion has been observed in women compared to men.6, 7, 8 The relationship between these alterations and sex-differences in the development of heart failure, particularly heart failure with preserved ejection fraction, remains unclear.
Three-dimensional (3D) echocardiography currently allows a more comprehensive characterization of cardiac kinematics based on 3D model, enabling simultaneous assessment of various myocardial systolic components as well as torsion mechanics using speckle-tracking.9 Such information may provide valuable insights into complex cardiac dynamics and may substantially improve the understanding of systolic function. We utilized 3D echocardiography obtained in a large community-based cohort to investigate gender-related differences in cardiac mechanics in an elderly community-based population without known prevalent heart failure.
Methods
Study Population and Patient Selection Criteria
The Atherosclerosis Risk in Communities (ARIC) Study is an ongoing, prospective observational study. Detailed study rationale, design, and procedures have been previously published.10 The original cohort included 15,792 men and women aged 45 to 64 years recruited between 1987 and 1989 (visit 1), selected from 4 communities (Forsyth County, NC; Jackson, MS; Minneapolis, MN; and Washington County, MD) in the United States. The overall ARIC Study had follow-up visits (visit 2–4) at 3-year intervals through 1996–1998. In 2011 and 2013, a total of 6,101 surviving participants underwent Visit 5, when echocardiography was performed in all 4 ARIC field centers. The current study comprised participants attending ARIC’s 5th visit without prevalent HF during the study period and were restricted to a subset of 3,035 ARIC participants from the first half of Visit 5 (until December 2012) as published elsewhere.11
Baseline demographic information, anthropometric data and blood sampling were obtained within this visit. Institutional review boards from each site approved the study, and informed consent was obtained from all participants. Medical history including hypertension (HTN), diabetes (DM), dyslipidemia or coronary heart disease (CHD) was obtained using standardized and validated interviewer-administered questionnaires as previously described.12 Hypertension was defined as systolic blood pressure ≥140 or diastolic blood pressure ≥90, or medication use for high blood pressure during the last 4 weeks before visit. Laboratory testing including total cholesterol, triglyceride, and high-density lipoprotein cholesterol were measured in a centralized laboratory, with N-terminal pro-brain natriuretic peptide (NT-proBNP). Renal function in terms of estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease (MDRD) Study equation. We excluded subjects with atrial fibrillation or other arrhythmias, as frequent ventricular premature beats or supra-ventricular tachy-arrhythmias that may potentially lead to irregular heart cycles and 3D echocardiography artifacts; participants who underwent valvular replacement surgery, those with moderate or severe valvular heart diseases, left bundle branch block, severe pulmonary hypertension (systolic pulmonary artery pressure ≥60mmHg), and those who underwent pacemaker or defibrillator implant that could cause alterations of LV contractile patterns. The total sample for current 3D echocardiography analysis included 1,105 asymptomatic participants with satisfactory 3D imaging quality after exclusion. (Supplemental Materials).
Echocardiography Protocol
Two-Dimensional Echocardiography and Diastolic Functional Assessment
Baseline transthoracic 2D echocardiography was performed at each study site utilizing commercial ultrasound machines (iE33, Philips Medical Systems with Vision 2011) by experienced technicians following preprogrammed acquisition protocol. All images were then stored digitally and transferred from field centers to a secure Echocardiography Reading Center (Brigham and Women’s Hospital, Boston, MA), where all echo-derived measures were carried out with standard protocol and over-read blinded to study participants’ clinical information.13
All Left atrial (LA) and LV volumes, end-diastolic volume (EDV)/end-systolic volume (ESV), and derived LV stroke volume (SV) or LV ejection fraction (LVEF) were measured by the biplane modified Simpson’s method using apical 4- and 2-chamber views. LV mass was assessed from LV lieanr dimensions using the formula recommended by the American Society of Echocardiography and indexed to body surface area. Right ventricular (RV) function was measured by RV fractional area (RV FAC) calculated by percentage of changes in cavity area between end-diastolic and end-systolic phases from apical 4-chamber view. All 2D and Doppler images, including mitral inflow E and A with the derived E/A ratio, deceleration time and averaged (septal and lateral) early diastolic myocardial velocity E′ by tissue Doppler imaging14 were reviewed for imaging quality and were analyzed by a trained investigator at the core lab.
Three-Dimensional Echocardiography
Three-dimensional Echocardiography(3DE) image was acquired using wide-angle mode with 4 wedge-shaped pyramidal sub-volumes (93° × 21°), during a single breath hold over 4 consecutive cardiac cycles at a frame rate of 15–25 Hz (X3-1 transducer) depending on the selected line density. 3D models of LV segmental time–strain curves were generated by automatic edge detection using an off-line, semi-automated contour-tracking and quantification algorithm (4D LV analysis 2.0, TomTec, Unterschleissheim, Germany) that divided the LV cast into 16-segment time curves for regional and global strain analysis (both longitudinal [GLS] and circumferential [GCS]), with minimal manual correction when necessary (Supplemental Material: Figure 1A–D). LV twist and torsion (twist per length, degree/cm or °/cm) were also provided by the software (Supplemental Material: Figure 1E). Less negative GLS and GCS indicate a functional decline in global myocardial deformation assessment, with more positive twist/torsion values representing better torque mechanics. We also calculated torsion-to-circumferential ratio (TCR), a theoretically more standardized torsion measure independent of LV cavity size variations and contractility.15–17 TCR had been shown to be near constant among healthy individuals of same age and proposed to increase with aging or subendocardial dysfunction.3,7 3D-based LV mass and mass-to-volume (MV) ratio were further analyzed by commercial software and presented. Detailed image quality scoring, analysis and reproducibility of 3D-based strain, twist/torsion and mass measures were further mentioned in supplemental materials. All 3D images and related indexes were analyzed at the core laboratory at the BWH blinded to the clinical information.
Statistical Analysis
Continuous data are presented as mean and the standard deviation (SD) unless otherwise specifically indicated, and categorical variables are presented as proportions or percentages in distributions. Cuzick’s nonparametric trend test across ordered age-stratified quintile groups (67–70, 71–73, 73–76, 76–80, and ≥ 80) were used to test for trends in demographic characteristics and echocardiography-derived measures or indices with Cochran-Armitage test used for the trend for proportional distributions of cardiovascular risk factors as dichotomous variables among groups, respectively. The associations among 3DE-derived torsion indices including twist, torsion, TCR and baseline demographics or conventional echocardiography parameters were assessed by Pearson correlation (Supplemental Table 1).
We further tested the relationship between age (per decade change) (independent variable) and measures of conventional echocardiography and 3DE-derived strain or torsion indices (dependent variables) including twist, torsion, and TCR using linear regression models. These associations were further adjusted for clinical covariates (CV) (gender, ethnicity, systolic blood pressure, heart rate, estimated glomerular filtration rate [eGFR]), medical history of hypertension, diabetes, hyperlipidemia, and coronary heart disease. Multivariable models were further adjusted for LV geometric parameters including stroke volume (SV) and mass-to-volume (MV) ratio. As an a priori hypothesis, we also tested whether the associations between 3DE-derived strain or torsional mechanics and aging may vary with sex; tests for interaction were performed with or without interaction terms between sex and torsion indices with aging in our models.
A two-sided p value less than 0.05 was used to determine the statistical significance level (95% CI). Statistical analyses were performed with STATA software (version 11.0, Stata-Corp., College Station, TX, USA) and SAS (version 9.2, NC, USA).
Results
Age and Gender-related Differences on Baseline Demographics and Conventional LV Structure and Function
Table 1 illustrates the characteristics of the 1,105 participants included in this study (mean age: 76±5 years, 60% women), categorized by age quintiles. Increasing age was associated with a decrease in BMI, higher blood pressure components (systolic and pulse pressures), lower heart rate, lower eGFR, lower total cholesterol level, and higher NT-proBNP (p for all trends < 0.05). In addition, a trend toward higher prevalence of hypertension and CHD was observed among older individuals, while there was no significant difference regarding age, systolic blood pressure, hypertension or diabetes by gender for all participants.
Table 1.
Baseline characteristics and demographic information of the study samples based on age quintiles groups
| Quintile 1 | Quintile 2 | Quintile 3 | Quintile 4 | Quintile 5 | P Value* | |
|---|---|---|---|---|---|---|
|
| ||||||
| Age range, mean (SD) | 221 (67 – 70 y/o) | 220 (71 – 73 y/o) | 222 (73 – 76 y/o) | 221 (76 – 80 y/o) | 221 (80 – 89 y/o) | |
| Baseline Characteristics | ||||||
| Female (%) | 137(62.0) | 139(63.2) | 140(63.1) | 126(57.0) | 128(57.9) | 0.16 |
| White (%) | 187(84.6) | 184(83.6) | 191(86) | 197(89.1) | 189(85.5) | 0.33 |
| Centre, n (%) | ||||||
| Forsyth County, NC | 103(46.6) | 90(40.9) | 94(42.3) | 104(47.3) | 103(46.6) | 0.52 |
| Jackson, MS | 25(11.3) | 29(13.2) | 25(11.3) | 18(8.2) | 21(9.5) | |
| Minneapolis, MN | 44(19.9) | 46(20.9) | 51(23.0) | 51(23.2) | 35(15.8) | |
| Washington County, MD | 49(22.2) | 55(25.0) | 52(23.4) | 47(21.3) | 62(28.1) | |
| BMI, kg/m2 | 27.9(5.4) | 27.6(5.1) | 27.0(4.4) | 26.8(5.0) | 26.4(4.1) | 0.005 |
| SBP, mmHg | 124.5(16.2) | 130.3(18.3) | 132.7(16.4) | 133.0(17.0) | 136.8(18.2) | <0.001 |
| DBP, mmHg | 68.7(10.1) | 68.2(10.5) | 67.6(9.5) | 66.1(10.2) | 65.5(10.3) | 0.003 |
| PP, mmHg | 55.7(11.6) | 62.0(14.4) | 65.0(14.1) | 66.9(12.9) | 71.3(14.6) | <0.001 |
| HR, bpm | 66.2(9.9) | 64.3(10.0) | 63.6(10.1) | 62.4(10.2) | 63.6(10.3) | 0.003 |
| Glucose, mg/dL | 113.5(27.3) | 113.2(29.0) | 114.5(31.6) | 108.8(21.5) | 109.6(18.5) | 0.17 |
| Total cholesterol, mg/dL | 209.8(49.9) | 201.6(48.3) | 200.0(45.3) | 195.3(45.6) | 193.4(47.4) | <0.001 |
| eGFR, ml/min/1.73m2 | 78.4(15.0) | 73.2(14.9) | 71.1(15.5) | 70.3(15.1) | 64.3(16.9) | <0.001 |
| Hemoglobin, g/dL | 13.4(1.4) | 13.4(1.3) | 13.3(1.3) | 13.3(1.3) | 13.1(1.3) | 0.022 |
| NT-proBNP, mmol/L† | 74.8[47.8, 133.3] | 98.4[50.4, 160.3] | 126.3[77.3, 193.4] | 150.5[84.1, 240.9] | 168.9[100.4, 312.2] | 0.005 |
| Hypertension, n (%) | 133(60.2) | 149(67.7) | 158(71.2) | 163(74.1) | 180(81.5) | <0.001 |
| Diabetes, n (%) | 48(21.7) | 60(27.3) | 44(19.8) | 38(17.3) | 52(23.5) | 0.47 |
| Hyperlipidemia, n (%) | 92(43.8) | 107(49.8) | 96(45.1) | 112(51.4) | 105(49.1) | 0.20 |
| CHD, n (%) | 12(5.4) | 17(7.7) | 13(5.9) | 25(11.3) | 36(16.3) | <0.001 |
| Conventional Echocardiography | ||||||
| EDV, mL | 84.3(22.9) | 82.7(23.3) | 81.9(22.7) | 82.0(22.6) | 79.1(22.2) | 0.029 |
| ESV, mL | 28.3(9.7) | 27.4(10.0) | 26.9(9.5) | 27.7(10.6) | 26.1(9.8) | 0.03 |
| SV, mL | 56.1(14.8) | 55.3(14.8) | 55.0(14.8) | 54.1(13.4) | 53(14.2) | 0.032 |
| LV EF, % | 66.7(5.1) | 67.3(5.0) | 67.6(5.2) | 66.7(4.9) | 67.5(5.6) | 0.34 |
| IVS, cm | 1.03(0.15) | 1.05(0.16) | 1.04(0.17) | 1.07(0.15) | 1.10(0.15) | <0.001 |
| LVPW, cm | 0.88(0.13) | 0.88(0.14) | 0.88(0.13) | 0.92(0.14) | 0.90(0.13) | 0.003 |
| LV Mass Index, gm/m2 | 74.3(16.6) | 76(17.1) | 75.7(18.1) | 80.3(18.8) | 80.2(18.3) | <0.001 |
| LV Mass Index (3D), gm/m2 | 67.3(11.8) | 68.4(13.3) | 69.4(14.1) | 70.5(12.7) | 71.5 (13.8) | <0.001 |
| MV Ratio | 1.70(0.42) | 1.75(0.45) | 1.77(0.47) | 1.85(0.45) | 1.88(0.47) | <0.001 |
| MV Ratio (3D) | 1.64(0.28) | 1.70(0.29) | 1.74(0.39) | 1.76(0.31) | 1.83(0.34) | <0.001 |
| RV diastolic area, cm2 | 20(5.2) | 19.3(5.3) | 20.5(5.4) | 20.8(5.4) | 19.6(5.2) | 0.51 |
| RV FAC | 0.53(0.08) | 0.54(0.08) | 0.55(0.08) | 0.54(0.08) | 0.54(0.08) | 0.09 |
| 2D LA Vol/index, mL/m2 | 24.5(6.3) | 25.2(6.4) | 26.1(7.3) | 26.5(7.2) | 27.5(8.0) | <0.001 |
| E/A Ratio | 0.96(0.30) | 0.91(0.25) | 0.91(0.29) | 0.86(0.26) | 0.83(0.28) | <0.001 |
| DT, ms | 209.8(45.1) | 211.1(49.3) | 222.5(46.5) | 222.7(48.3) | 224.4(50.2) | <0.001 |
| E′ (mean), cm/sec | 7.13(1.52) | 6.67(1.51) | 6.59(1.36) | 6.14(1.37) | 5.8(1.46) | <0.001 |
| E/E′ Ratio | 9.26(3.28) | 9.73(3.21) | 9.92(3.61) | 10.77(3.64) | 11.5(4.26) | <0.001 |
BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, PP: pulse pressure;
CHD: coronary heart disease, DT: deceleration time, eGFR: estimated glomerular filtration rate, E/E′: early mitral inflow velocity (E) divided by averaged mitral annulus LV E′, EA Ratio: early to late mitral inflow velocity ratio, FAC: fractional area change, IVS: left ventricular interventricular septum wall thickness, LA: left atrial, LVEDV: left ventricular end-diastolic volume, LVESV: left ventricular end-systolic volume, LV EF: left ventricular ejection fraction, LV E′ (mean): averaged septal and lateral mitral annulus early diastolic relaxation velocity E′, LVPW: left ventricular posterior wall thickness, LV SV: left ventricular stroke volume, MV Ratio: ventricular mass-to-volume ratio, RV: right ventricular.
P value for trend across age categories,
Data are described as median and [25th ~ 75th] percentile,
SD: standard deviation.
Overall, older age was associated with smaller LV EDV and ESV, lower LV SV, greater wall thicknesses and larger LV mass index, resulting in greater LV concentricity in terms of higher MV ratio (Table 2). Increasing age was also associated with larger indexed LA volume, more prolonged mitral inflow deceleration time, lower E/A ratio, lower mitral annulus relaxation velocity E′, and higher E/E′ ratio (all p < 0.05) though unchanged RV area, RV FAC, or global LVEF (Table 1). The associations between older age and these LV structural/functional changes remained significant in multivariable models after accounting for baseline clinical covariates. In general, women showed significantly smaller LV EDV, SV, higher LVEF, greater LV MV ratio and lower myocardial relaxation velocity E′ than men (all p < 0.001) (Table 2). Conversely, men had greater LV wall thickness and larger LV mass index than women (both p < 0.001) (Table 2). Finally, sex did not modify the effects of increasing age on these LV geometric parameters.
Table 2.
Associations among age, gender, conventional echocardiography and cardiac torsional mechanics
| Age (per decade change) | Gender: Female (vs Male) | |||||||
|---|---|---|---|---|---|---|---|---|
| Univariable Analysis | Multivariable Analysis | Univariable Analysis | Multivariable Analysis | |||||
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|
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| Coefficient (95% CI) | p value | Coefficient (95% CI) | p value | Coefficient (95% CI) | p value | Coefficient (95% CI) | p value | |
|
|
|
|
|
|||||
| Conventional Echocardiography | ||||||||
| EDV, mL | −3.24(−5.8, −0.68) | 0.013 | −3.09(−5.34, −0.84) | 0.007 | −27.4(−29.6, −25.2) | <0.001 | −26.6(−28.9, −24.3) | <0.001 |
| ESV, mL | −1.14(−2.24, −0.03) | 0.044 | −1.06(−2.15, 0.02) | 0.054 | −10.83(−11.83, −9.84) | <0.001 | −10.69(111.79, 19.58) | <0.001 |
| SV, mL | −2.11(−3.74, −0.47) | 0.011 | −2.02(−3.47, −0.58) | 0.006 | −16.57(−18.01, −15.13) | <0.001 | −15.93(−17.4, −14.46) | <0.001 |
| LV EF, % | 0.19(−0.4, 0.78) | 0.528 | 0.20(−0.50, 0.89) | 0.58 | 2.13(1.52, 2.74) | <0.001 | 2.35(1.65, 3.06) | <0.001 |
| IVS, cm | 0.05(0.03, 0.07) | <0.001 | 0.05(0.03, 0.07) | <0.001† | −0.07(−0.09, −0.05) | <0.001 | −0.07(−0.09, −0.05) | <0.001† |
| LVPW, cm | 0.02(0.005, 0.04) | 0.01 | 0.01(−0.006, 0.03) | 0.19† | −0.07(−0.08, −0.05) | <0.001 | −0.07(−0.09, −0.05) | <0.001† |
| LV Mass Index, gm/m2 | 4.43(2.33, 6.54) | <0.001 | 2.27(0.003, 4.54) | 0.05† | −8.56(−10.78, −6.34) | <0.001 | −7.26(−9.58, −4.94) | <0.001† |
| LV Mass Index (3D), gm/m2 | 2.79(1.29, 4.30) | <0.001 | 1.47(−0.17, 3.12) | 0.079† | −8.80(−10.32, −7.28) | <0.001 | −7.88(−9.56, −6.21) | <0.001† |
| MV Ratio | 0.12(0.07, 0.17) | <0.001 | 0.08(0.03, 0.14) | 0.005† | 0.15(0.10, 0.21) | <0.001 | 0.17(0.11, 0.23) | <0.001† |
| MV Ratio (3D) | 0.11(0.07, 0.14) | <0.001 | 0.10(0.06, 0.15) | <0.001† | 0.07(0.03, 0.11) | 0.001 | 0.05(0.01, 0.10) | 0.018† |
| RV diastolic area, cm2 | 0.12(−0.53, 0.77) | 0.713 | 0.27(−0.36, 0.90) | 0.395 | −4.9(−5.52, −4.28) | <0.001 | −4.45(−5.10, −3.81) | <0.001 |
| RV FAC | 0.004(−0.005, 0..01) | 0.399 | −0.003(−0.01, 0.008) | 0.629 | 0.03(0.02, 0.04) | <0.001 | 0.03(0.02, 0.04) | <0.001 |
| 2D LA Vol/index, mL/m2 | 2.11(1.31, 2.91) | <0.001 | 1.38(0.48, 2.28) | 0.003† | −1.68(−2.53, −0.82) | <0.001 | −0.69(−1.61, 0.23)† | 0.14† |
| E/A Ratio | −0.09(−0.12, −0.06) | <0.001 | −0.09(−0.13, −0.06) | <0.001 | −0.03(−0.06, 0.009) | 0.152 | 0.01(−0.02, 0.05) | 0.53 |
| DT, ms | 9.69(4.24, 15.14) | 0.001 | 7.7(1.33, 14.07) | 0.018 | −15.1(−20.87, −9.34) | <0.001 | −10.46(−16.96, −3.96) | 0.002 |
| E′ (mean), cm/sec | −0.88(−1.04, −0.72) | <0.001 | −0.84(−1.03, −0.64) | <0.001† | −0.32(−0.51, −0.14) | <0.001 | −0.41(−0.60, −0.21) | <0.001† |
| E/E′ Ratio | 1.65(1.23, 2.08) | <0.001 | 1.41(0.94, 1.87) | <0.001† | 1.75(1.29, 2.21) | <0.001 | 2.02(1.55, 2.50) | <0.001† |
| Deformation or Torsion Indexes | ||||||||
| Longitudinal Strain, % | 0.65(0.33, 0.97) | <0.001 | 0.39(0.02, 0.76) | 0.038† | −0.78(−1.12, −0.44) | <0.001 | −0.76(−1.13, −0.38) | <0.001† |
| Circumferential Strain, % | −0.76(−1.36, −0.17) | 0.012 | −0.59(−1.29, 0.10) | 0.08 | −2.0(−2.63, −1.37) | <0.001 | −2.00(−2.71, −1.29) | <0.001 |
| Twist, degree | 2.01(1.58, 2.45) | <0.001 | 2.06(1.55, 2.57) | <0.001※† | 1.63(1.16, 2.10) | <0.001 | 1.74(1.22, 2.26) | <0.001※† |
| Male | 2.35(1.65, 3.05) | <0.001 | ||||||
| Female | 1.71(0.98, 2.45) | <0.001 | ||||||
| Torsion, degree/cm | 0.33(0.26, 0.39) | <0.001 | 0.33(0.26, 0.4) | <0.001※† | 0.41(0.34, 0.47) | <0.001 | 0.42(0.35, 0.49) | <0.001※† |
| Male | 0.27(0.18, 0.36) | <0.001 | ||||||
| Female | 0.38(0.28, 0.48) | <0.001 | ||||||
| TCR, degree*%/cm | −0.95(−1.16, −0.73) | <0.001 | −1.01(−1.26, −0.76) | <0.001※† | −1.03(−1.26, −0.80) | <0.001 | −1.07(−1.32, −0.82) | <0.001※† |
| Male | −0.85(−1.19, −0.50) | <0.001 | ||||||
| Female | −1.12(−1.47, −0.78) | <0.001 | ||||||
The estimate for age was adjusted for gender, race, systolic blood pressure, BMI, heart rate, renal function (eGFR), history of hypertension, diabetes, hyperlipidemia medication use, and history of coronary heart disease;
The estimate for gender was adjusted for age, race, systolic blood pressure, BMI, heart rate, renal function (eGFR), history of hypertension, diabetes, hyperlipidemia medication use, and history of coronary heart disease;
interaction p for age x sex <0.05 in multivariable models;
systolic blood pressure was independently significant (p<0.05).
Associations between Age or Gender on Myocardial Deformations and Torsion Mechanics
Greater age was associated with lower LS, greater GCS, lower myocardial relaxation velocity E′, though marked increase of twist, torsion or TCR (Figure 1, all trend p<0.05). While we demonstrated substantial worsening of both lower mitral annulus relaxation velocity E′ and GLS accompanied by higher MV ratio and smaller LV SV with increasing age, LVEF remained unchanged (Figure 2A and B). Age, female gender, and higher systolic/pulse pressures were strongly related to greater twist/torsion mechanics (Table 2 & Supplemental Material: Table 1). Further, age-related cardiac structural remodeling in terms of greater MV ratio was related to reduced GLS and greater twist/torsion mechanics (Figure 2C, Table 3 & Supplemental Material: Table 1, all p<0.05).
Figure 1. Associations among age, measurement of LV mechanics or torsion.
Graded reduction of longitudinal systolic shortening including lower longitudinal strain (LS) and lower mitral annulus relaxation velocity E′, as well as modest increase of circumferential fiber shortening (GCS) were shown by age quintiles, which were accompanied by larger LV torsion indices. All strain data and TCR are negative and presented as absolute values. (Linear trend of p for all: < 0.05)
Figure 2. Associations among age, cardiac remodeling, and sex-differences in LV torsion.
Increasing age was associated with greater LV concentric remodeling, lower E′(A), lower GLS and unchanged LVEF with markedly higher torsion, which was more pronounced in women (B) (sex interaction for torsion with age: p<0.05). Greater LV MV ratio with advanced age was associated with smaller LV SV (r=-0.42, p<0.001), worse GLS (r=0.19, p<0.001) and higher LV torsion (C) (r=0.22, p<0.001), though no gender differences observed in torsion (sex interaction: p=0.251). All strain data are negative and presented as absolute values.
Table 3.
Associations among age, gender, and cardiac torsional mechanics after accounting for LV geometry parameters
| Age (per decade change) | Gender: Female (vs Male) | |||||
|---|---|---|---|---|---|---|
| Overall | Male | Female | Overall | |||
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| Multivariable Models | Coefficient (95% CI) | p value | Coefficient (95% CI) | Coefficient (95% CI) | p value | |
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|||||
| Longitudinal Strain, % | ||||||
| + SV | 0.39(0.03, 0.77) | 0.036† | −0.72(−1.18, −0.26) | 0.002† | ||
| + MV Ratio | 0.33(−0.04, 0.69) | 0.08¥† | −0.92(−1.30, −0.54) | <0.001¥† | ||
| + MV Ratio (3D) | 0.36(−0.02, 0.73) | 0.06¥† | −0.78(−1.16, −0.41) | <0.001¥† | ||
| Circumferential Strain, % | ||||||
| + SV | −0.56(−1.26, 0.14) | 0.12 | −1.84(−2.71, −0.97) | <0.001 | ||
| + MV Ratio | −0.54(−1.24, 0.16) | 0.13 | −1.90(−2.62, −1.18) | <0.001 | ||
| + MV Ratio (3D) | −0.25(−0.95, 0.44) | 0.47¥ | −1.84(−2.54, −1.14) | <0.001¥ | ||
| Twist, degree | ||||||
| + SV | 2.05(1.53, 2.56) | <0.001※† | 1.69(0.95, 2.43) | 2.34(1.63, 3.04) | 1.61(0.97, 2.25) | <0.001† |
| + MV Ratio | 2.03(1.51, 2.54) | <0.001※† | 1.70(0.96, 2.44) | 2.30(1.60, 3.00) | 1.66(1.31, 2.19) | <0.001† |
| + MV Ratio (3D) | 1.93(1.41, 2.44) | <0.001¥† | 1.73(0.98, 2.48) | 2.12(1.43, 2.82) | 1.67(1.16, 2.19) | <0.001¥† |
| Torsion, degree/cm | ||||||
| + SV | 0.32(0.25, 0.39) | <0.001¥†※ | 0.26(0.17, 0.35) | 0.37(0.27, 0.47) | 0.34(0.25, 0.43) | <0.001¥ |
| + MV Ratio | 0.32(0.25, 0.39) | <0.001¥※ | 0.26(0.17, 0.35) | 0.36(0.26, 0.46) | 0.40(0.32, 0.47) | <0.001¥ |
| + MV Ratio (3D) | 0.30(0.23, 0.37) | <0.001¥ | 0.26(0.17, 0.36) | 0.33(0.24, 0.43) | 0.41(0.33, 0.48) | <0.001¥ |
| TCR, degree*%/cm | ||||||
| + SV | −0.98(−1.23, −0.73) | <0.001¥※ | −0.80(−1.14, −0.46) | −1.11(−1.46, −0.77) | −0.85(−1.15, −0.54) | <0.001¥ |
| + MV Ratio | −0.98(−1.23, −0.73) | <0.001¥※ | −0.84(−1.18, −0.49) | −1.09(−1.43, −0.74) | −1.01(−1.27, −0.76) | <0.001¥ |
| + MV Ratio (3D) | −0.99(−1.24, −0.74) | <0.001¥ | −0.90(−1.24, −0.55) | −1.07(−1.42, −0.73) | −1.06(−1.32, −0.74) | <0.001¥ |
The estimate for age was adjusted for gender, race, systolic blood pressure, BMI, heart rate, renal function (eGFR), history of hypertension, diabetes, hyperlipidemia medication use, and history of coronary heart disease;
The estimate for gender was adjusted for age, race, systolic blood pressure, BMI, heart rate, renal function (eGFR), history of hypertension, diabetes, hyperlipidemia medication use, and history of coronary heart disease;
interaction p for age x sex <0.05 in multivariable models;
systolic blood pressure was independently significant (p<0.05);
LV geometric parameters (eg.. SV, MV ratio) were significant (p<0.05).
After accounting for clinical covariates, the associations between advanced age and lower GLS (adjusted estimate: 0.39±0.19% (SE)/decade, p=0.038), higher twist or torsion (adjusted estimate: 2.06 ± 0.26° (SE)/decade, 0.33 ± 0.04°/cm (SE)/decade), and TCR (adjusted estimate: −1.01 ± 0.13 degree*%/cm (SE)/decade, all p<0.001) all remained significant, with a borderline increase in GCS (adjusted estimate: −0.59±0.35% (SE)/decade, p=0.08). These associations remained unchanged even after accounting for LV geometric parameters (Table 3).
Compared to men, women showed greater GLS and GCS (− 0.78% and − 2.00%, respectively, both p<0.001) and demonstrated a more pronounced increase of torsion with advanced age (men vs women: 0.27 ± 0.05°/cm vs 0.38 ± 0.05°/cm (SE)/decade, respectively, p for interaction < 0.05) (Figure 2B), even after accounting for clinical co-variates and LV geometry (Table 3). Similar trends were observed for twist and TCR (Figure 1, p for interaction < 0.05 & Table 3). Finally, subjects with hypertension showed significantly greater wall thickness, greater LV mass index and MV ratio, worse diastolic function, lower GLS, though significantly greater twist/torsion (Supplemental Material: Table 2).
Discussion
In this study, we explored cardiac mechanics in a large community population using advanced 3D-based speckle-tracking. Overall, we observed sex-related distinct cardiac remodeling patterns with increasing age in this elderly cohort, with women demonstrating greater concentric remodeling, smaller LV size and better contractile function compared with men. We further demonstrated that such age-related cardiac remodeling was associated with diastolic functional alterations and reduced longitudinal motion, which appeared to be compensated by modest increases in circumferential fiber shortening and greater torsion leading to unchanged global LV pump function. Finally, sex-related torsion differences in this elderly population appeared to be independent of LV geometric alterations.
Cardiac Twist/Torsion Analysis by 3DE Speckle Tracking Technique
It has been proposed that longitudinal atrial-ventricular motion may account for nearly 60% of cardiac stroke volume, with the remaining part contributed by circumferential function and wringing motion.18 A dynamic wringing movement, defined by simultaneous shortening of obliquely oriented helical (left-handed in epicardial and right-handed at endocardial) myofibers in opposite directions during ejection, has been shown to generate equilibrated myocardial sarcomere shortening to minimize wall stress.3 LV torsion analysis by 2D speckle-tracking technique has been clinically feasible and has yielded promising insights into global systolic function,19–21 but may be limited due to the architecturally three-dimensional nature of myocardial contraction.22 These limitations can be largely overcome with 3D-based tracking,5,9,22,23
Cardiac Remodeling, Mechanics and Torsion Changes during Aging
Consistent with prior reports, we observed that cardiac torsion may be augmented with increasing age.3,5,7,24 It has been proposed that biological senescence and associated co-morbidities with or without superimposed hemodynamic burden are associated with LV concentric remodeling2, which may be accompanied by intrinsic cardiac functional decline, 25 lower LV diastolic relaxation velocity and subendocardial pathology.1,3,5 While torsion is primarily formed by the mechanical dominance of helical, counteracting epicardial (left-handed) over endocardial layers (right-handed) during contraction, greater distance between layers (e.g. greater wall thickness and smaller cavity radius in concentric hypertrophy) may therefore augment torsion (lever-arm theory).7,19 Thus, greater concentricity with aging may enhance torsion by this mechanism.
As mentioned above, enhanced torsion with age-related concentric remodeling may act to compensate for progressive subendocardial pathologies, as evidenced by diminished longitudinal deformation and greater TCR.3,7,26 The independent link between increasing age and higher torsion or TCR, rather than circumferential strain, further supports the concept that torsion formation is more likely driven by factors beyond short-axis adaptations per se.
Cardiac Adaptations, Mechanics and Torsion in Hypertension
We observed that hypertension was associated with worse longitudinal function and greater torsion indices, though its relationship with longitudinal functional decline became attenuated after adjusting for LV geometry. The possible reasons underlying greater torsion in subjects with hypertension can be in part due to exaggerated cardiomyocytes fibrosis, extra-cellular matrix deposition, and subsequent concentric remodeling.2,25 Further, certain pathological or subclinical ischemic changes tend to be more common in the elderly population, which in turn may aggravate functional decay in more longitudinally oriented endocardium with excessive load; in this regard, forces opposing epicardial layer function are reduced and further favor greater torsion.3,4,7,26 In this manner, a biological paradox may happen with greater torsion formation in the presence of increased concentricity despite concurrently compromised longitudinal myofiber shortening.
Sex-differences on Cardiac Remodeling, Mechanics and Torsion
Consistent with prior reports, we showed sex-related differences of cardiac remodeling and myocardial deformation in our elderly population.27,28 Higher rate of cardiomyocyte turn-over, apoptosis and fibrosis with aging in males may in part explain greater chamber size, higher cardiac mass and lower intrinsic contractile function compared to women.6,29,30 Moreover, the significantly smaller LV volumes in women compared to men might justify the requirement for higher systolic function and greater torsion to provide adequate cardiac output and to meet tissue metabolic demand.
While women tend to adapt to chronic pressure overload by having greater degree of concentric hypertrophy and better contractile reserve, men tend to manifest as contractile dysfunction and greater eccentricity.6,31,32 It has also been proposed that loss of estrogen protection may accentuate LV hypertrophy with pressure overload in elderly females31,33. Augmented torsion in response to load-related concentric hypertrophy may further facilitate transverse shear to reduce wall stress and contribute to wall thickening during the ejection phase.17,33 These in turn results in minimal oxygen expenditure and yet to preserve global LV pump functions with excessive load34. Taken together, a better LV systolic function and greater torsion can therefore be observed in women when compared to men. While others have previously attributed sex differences of torsion to LV geometric alterations,7 we found that gender differences in torsion remain unchanged after adjusting for LV geometric effects.
Limitations
Our current work has several limitations: First, our findings are cross-sectional and have no longitudinal tracking data; therefore the causal relationships between altered cardiac deformation or torsion indices with respect to aging or higher blood pressure cannot be confirmed. Second, the proportion of images suitable for the 3D tracking was limited by the quality of the 3D images. Nonetheless, there were no remarkable differences in clinical and demographic characteristics between patients with or without analyzable 3D echocardiography data. Further, data from 3D speckle-tracking in our work should not be interpreted interchangeably with 2D methods. Finally, our results should be interpreted with caution and limited generalizability because our study population had advanced age and was predominantly white, and the real influences of subclinical ischemia in determining part of the observed functional alterations attributed to senescence could not be ascertained.
Conclusions
We demonstrated that in a senescent community-dwelling population, reduced diastolic relaxation and LV longitudinal shortening was counterbalanced by augmented torsion mechanics, a finding that was more prominent in women than in men. Taken together, these findings further highlighted gender-specific cardiac responses to aging.
Supplementary Material
Clinical Perspective.
Cardiac torsion is a key systolic element in cardiac mechanics contributing to cardiac output and ejection performance. Senescence, elevated hemodynamic load, and female sex have all been traditionally recognized as important risks for HFpEF in prior large epidemiologic studies. Our data shows that in an asymptomatic elderly community cohort, the relative increase of cardiac torsion with advanced age and elevated load may play a central role in maintaining adequate cardiac output or pumping. Moreover, we also demonstrated greater systolic indices from all aspects and a marked increase in torsion among aged women, which may in part explain the sex differences of cardiac adaptation to aging.
Acknowledgments
We would like to express our sincere gratitude to Brian Claggett for the professional help in statistics.
Sources of Funding
The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. The authors thank the staff and participants of the ARIC study for their important contributions. Dr. Gonçalves is supported by the Portuguese Foundation for Science and Technology Grant HMSP-ICS/007/2012. This work was also supported NHLBI cooperative agreement NHLBI-HC-11-08 (S. D. S.), grants K08-HL-116792 (A. M. S.) and R00-HL-107642 (S. C.), and a grant from the Ellison Foundation (S. C.).
Footnotes
-
Chung-Lieh Hung: No disclosuresGrant from the Macky Memorial Hospitaljotaro3791@gmail.comAddress: Mackay Memorial Hospital, Cardiovascular Division, 92, Chung-Shan North Road, 2nd section, Taipei, Taiwan, ROC
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Alexandra Gonçalves: No disclosuresDr. Gonçalves is supported by the Portuguese Foundation for Science and Technology Grant HMSP-ICS/007/2012alexandra.mgsg@gmail.comAddress: Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis Street, Boston, MA 02115
-
Amil M Shah: No disclosuresDr. Shah is supported by a grant from K08-HL-116792ashah11@rics.bwh.harvard.eduAddress: Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis Street, Boston, MA 02115
-
Susan Cheng: No disclosuresDr. Cheng is supported by a grant from R00-HL-107642 and a grant from the Ellison Foundationscheng@research.bwh.harvard.eduAddress: Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis Street, Boston, MA 02115
-
Dalane Kitzman: No disclosuresdkitzman@wakehealth.eduAddress: Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157
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Scott D Solomon: No disclosuresDr. Cheng is supported by a grant from NHLBI cooperative agreement NHLBI-HC-11-08ssolomon@rics.bwh.harvard.eduAddress: Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis Street, Boston, MA 02115
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