Abstract
Objectives
Assess the effect of central and general obesity measures on long-term longitudinal changes in ventricular-arterial mechanics.
Background
Obesity, female sex and ventricular-arterial stiffening are associated with the development of heart failure with preserved ejection fraction (HFpEF). Fat distribution and chronic changes in body composition may impact longitudinal changes in LV properties, independent of arterial load.
Methods
Comprehensive echo-Doppler echocardiography was performed in 1402 subjects participating in a randomly-selected community-based study at two examinations separated by 4 years. From this population, 788 subjects had adequate paired data to determine LV end-systolic elastance (Ees), end-diastolic elastance (Eed) and effective arterial elastance (Ea).
Results
Over 4 years, Ea decreased by 3% in tandem with improved blood pressure control, while Ees and Eed increased by 14% and 8% (p<0.001). Greater weight loss over 4 years was associated with progressively greater decreases in Ea in men and women. After adjusting for Ea change, weight gain was correlated with increases in Eed in both women and men. Central obesity was associated with greater age-related increases in Ees in women but not in men, independent of arterial load, but central obesity did not predict changes in Eed or Ea.
Conclusion
Weight gain is associated with increases in LV diastolic stiffness, even after adjusting for changes in arterial afterload, while weight loss is associated with reductions in arterial stiffness. Age-related LV systolic stiffening is increased in women with central obesity but not men. Strategies to promote weight loss and reduce central adiposity may be effective to prevent HFpEF, particularly in women.
Keywords: Obesity, Ventricular stiffness, Aging, Heart failure, Vascular stiffness
Introduction
Obesity independently predicts incident heart failure (HF) (1-4). In cross sectional studies, increased waist circumference (WC) is associated with left ventricular (LV) diastolic dysfunction (DD) (5,6). DD and obesity are common in HF with preserved ejection fraction (HFpEF) and may be causally linked (7). Women display increased ventricular and arterial stiffness compared to men and are more likely to develop HFpEF than men. However, the complex relationships between aging, sex, adiposity and ventricular mechanics remain poorly understood.
LV stiffness (elastance) at end systole (Ees) and end diastole (Eed) increases with aging despite reductions in blood pressure and arterial afterload (effective arterial elastance, Ea) (8), suggesting that mechanisms other than elevated afterload are involved. Age-related LV stiffening is correlated with increases in total body mass, but it is unclear how much of this is due to weight-related alterations in (Ea), and the impact of fat distribution has not been assessed. In morbidly obese patients, weight loss prevents left atrial enlargement (9) and correlates with improvement in myocardial deformation (10), but little is known regarding the effects of fat distribution and long term weight changes in the community setting and in the absence of medically-complicated obesity.
Visceral fat mass is a major risk factor for cardiovascular disease (CVD) (11,12), while peripheral fat seems to confer a protective effect (13).We hypothesized that central obesity is more strongly associated with age-related LV stiffening, and that weight gain is associated with diastolic stiffening independent of load. To test these hypotheses, we assessed the associations between central and general obesity measures, weight change and longitudinal changes in ventricular-arterial coupling over four years using sex-specific analyses in a randomly-selected, community-based sample of the population.
Methods
Study Population
In 1997 a random sample of individuals residing in Olmsted County ≥45 years of age was identified by applying a sampling fraction of 7% within 5 year gender- and age-specific strata. 4203 persons were invited and 2042 participated in Exam 1 (1997-2000), which consisted of physical examination, echocardiography, and medical record abstraction. Comparison of invited participants with invited nonparticipants disclosed no difference in the prevalence of CVD, diabetes, or Charlson index (14). Four years later all participants were invited to return and 1402 participated in Exam 2 (2001-2004). Diabetes history was based on physician diagnosis and treatment. Myocardial infarction and hypertension were diagnosed according to criteria from the World Health Organization and the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, respectively. Some clinical and echocardiographic data from this population have been previously reported (6,8,15-17), but the current study findings regarding obesity measures and their influence on changes in ventricular-arterial stiffening over time have not been reported. The Institutional Review Boards of Mayo Clinic and Olmsted Medical Center approved this study. Participants provided written informed consent for evaluation and medical record follow-up.
Assessment of LV Structure and Function
Comprehensive echocardiographic assessment was performed by registered diagnostic cardiac sonographers using standardized instruments and techniques as previously described (16,18). Exam 1 and 2 echocardiograms were performed by the same three sonographers and reviewed by two cardiologists who were masked to clinical and Exam 1 echocardiogram findings. Ventricular dimensions, wall thickness, and chamber volumes were determined in triplicate from 2-dimensional echocardiography. LV EF was determined by the biplane Simpson's method. LV stroke volume (SV) was determined from pulse wave Doppler of the LV outflow tract. Cardiac output (CO) was determined as the product of stroke volume and heart rate. Brachial blood pressure (BP) was determined by sphygmomanometry. End-systolic pressure (ESP) was determined from the product of 0.9*systolic BP.
LV diastolic function was assessed by pulse wave Doppler examination of mitral inflow (E, A velocities, E/A ratio) and tissue Doppler examination of septal mitral annular velocities (e' velocity). The ratio of echo-Doppler and tissue-Doppler early diastolic velocities (E/e') was used to estimated LV end diastolic pressure (LVEDP) as previously validated (=11.96+0.596*E/e') (19). Operating LV end diastolic chamber stiffness (Eed) was estimated by the ratio of LVEDP and end diastolic volume (20). LV end systolic elastance (Ees) was determined by the single beat technique of Chen and colleagues based upon measured SV, EF, BP and systolic time intervals as previously reported (16,18,21).
Assessment of Arterial Function and Ventricular-Arterial Interaction
Effective arterial elastance (Ea), a measure of total arterial load that incorporates both mean and pulsatile components, was determined as ESP/SV (17). Systemic vascular resistance (=mean BP*80/CO) and total arterial compliance (=SV/pulse pressure) were determined as additional measures of arterial load. The ratio Ea/Ees was used to assess ventricular-arterial coupling (18).
Anthropometric measurements
Height and weight were measured with participants standing without shoes or heavy outer garments. Height was determined using a wall mounted stadiometer. Body weight was measured using a homologated electronic scale. Measurements were carried out by a trained research nurse with the subjects in the standing position. Body mass index (BMI) was calculated as weight/height2. Body circumferences were measured in centimeters using a non-elastic measuring tape: for waist at the top of umbilicus, for the hip at its maximal circumference, and for the neck at the lower half of the neck.
General obesity was defined as BMI >30 kg/m2. We used WC, waist-to-hip ratio and waist-to-height ratio as measures of central obesity, which are able to assess fat mass distribution and visceral fat mass better than BMI (22). Furthermore we used neck circumference as an additional measure of central obesity given that it is more closely related to visceral fat mass and metabolic abnormalities than WC (23,24).
Laboratory analysis
Laboratory analyses were performed at Mayo Clinic Rochester by experienced laboratory personnel. Glucose was measured on the Hitachi 912 Chemistry Analyzer using the hexokinase reagent from Boehringer Mannheim (Indianapolis, IN 46256). Insulin was determined using a specific two-site immunoenzymatic assay performed on the Access automated immunoassay system (Beckman Instruments, Chaska, MN 55318) that has a molar cross-reactivity of 0.10% with proinsulin. The HOMA2-IR index was obtained by the program HOMA Calculator (http://www.dtu.ox.ac.uk). Lipid analyses were performed using an automated enzymatic method. Adiponectin was measured using the Human Adiponectin Quantikine ELISA (R & D Systems, Minneapolis, MN) at the University of Minnesota, Minneapolis, MN. The interassay coefficient of variation was 5.5%.
Statistical methods
Data are expressed as mean ± SD, estimated marginal mean (95% confidence interval) or number (percentage). In graphs estimated marginal mean and SEM is plotted. Longitudinal changes in categorical variables were assessed with McNemar test and continuous variables by paired t-test or Wilcoxon signed-rank test, as appropriate. We used generalized mixed-effect regression models to test the difference in the rate of change of dependent variable by increase in independent variable. In these models, intercept was treated as a random factor, while time, obesity measures, the interaction term between time and obesity measures and other covariates were treated as fixed factors. The null hypothesis tested was that the change of slope with 1 unit increase in the obesity measure from exam 1 to exam 2 is equal to zero. Reported are coefficients with 95% confidence interval and a p value. In mixed-effect models, p-values (unadjusted for multiple comparisons) <0.05 were considered significant. For right-skewed data we used gamma regression. Models were compared by corrected Akaike information criterion (AIC). When gamma regression of the dependent variable is used, AIC is based on -2 log pseudo likelihood. Models with smaller AIC show better fit. Calculations were done using SPSS 19 (IBM Corporation, NY, USA). A two-sided p-value <0.05 was considered statistically significant.
Results
Of 1402 Olmsted County residents participating in examination 2, 788 had complete echocardiographic data to allow for assessment of Ees and Ea at both examinations. Subjects with adequate quality data were less obese compared to subjects without adequate data (Supplemental Table 1). The mean age of the subjects at examination 1 was 60 years and 48% were men (Table 1). Examination 2 was performed 4.0±0.3 years after examination 1. Descriptive statistics of the study sample at Exam 1 and 2 were previously reported (8). From examination 1 and 2, measures of both general and central obesity increased slightly but significantly (Table 1).
Table 1. Patient Characteristics at Study Entry and After 4 Years.
| Exam 1 (1997-2000) N=788 | Exam 2 (2001-2004) N=788 | p | |
|---|---|---|---|
| Men, n (%) | 375 (48) | 375 (48) | |
| Age, years | 60±9 | 64±9 | <0.0001 |
| Anthropometrics | |||
| Weight, kg | 80.02±17.01 | 80.45±17.05 | 0.02 |
| BMI, kg/m2 | 27.9±4.9 | 28.1±4.8 | <0.001 |
| BSA, m2 | 1.90±0.23 | 1.90±0.23 | 0.6 |
| Waist circumference (cm) | 90.10±13.94 | 92.95±14.73 | <0.0001 |
| Waist-hip ratio | 0.87±0.09 | 0.89±0.10 | <0.001 |
| Waist-height ratio | 0.53±0.07 | 0.55±0.09 | <0.0001 |
| Neck circumference (cm) | 36.55±4.26 | 37.57±4.4 | <0.0001 |
| Neck-height ratio | 0.21±0.02 | 0.22±0.03 | <0.0001 |
| Comorbidities | |||
| Obese, n (%) | 214 (27) | 213 (27) | 0.9 |
| Hypertension, n (%) | 204 (26) | 327 (41) | <0.0001 |
| Diabetes mellitus, n (%) | 45 (6) | 70 (9) | 0.02 |
| Coronary disease, n (%) | 79 (10) | 128 (16) | 0.0003 |
| Heart Failure, n (%) | 5 (0.6) | 8 (1) | 0.6 |
| Medications | |||
| ACEI/ARB, n (%) | 88 (12) | 172 (22) | <0.0001 |
| Beta blocker, n (%) | 123 (16) | 206 (26) | <0.0001 |
| Calcium channel blocker, n (%) | 56 (7) | 76 (10) | <0.0001 |
| Diuretic, n (%) | 142 (19) | 194 (25) | <0.0001 |
| Cardiovascular medication, n (%) | 312 (40) | 433 (55) | <0.0001 |
| Vital Signs | |||
| Heart rate (bpm) | 65±10 | 66±12 | 0.04 |
| Systolic BP (mmHg) | 130±20 | 126±19 | <0.0001 |
| Diastolic BP (mmHg) | 73±10 | 69±10 | <0.0001 |
| Mean BP (mmHg) | 92±12 | 88±12 | <0.0001 |
| Pulse pressure (mmHg) | 57±16 | 57±17 | 0.4 |
| Ventricular Structure & Function | |||
| LV end diastolic volume (ml) | 136±32 | 138±37 | 0.5 |
| LV septal wall thickness (mm) | 10.4±1.7 | 10.3±1.7 | 0.09 |
| LV posterior wall thickness (mm) | 9.6±1.3 | 9.3±1.2 | <0.0001 |
| Relative wall index | 0.40±0.06 | 0.38±0.06 | <0.001 |
| LV mass index (gm/m2) | 94.8±18.5 | 91.2±19.7 | 0.003 |
| LV ejection fraction (%) | 64±7 | 64±7 | 0.99 |
| E/e' ratio | 8.43±2.85 | 10.59±3.79 | <0.0001 |
| Estimated LVEDP (mmHg) | 16±1 | 18±2 | <0.0001 |
| Ventricular-Arterial Mechanics | |||
| Ea (mmHg/ml) | 1.39±0.34 | 1.36±0.36 | 0.003 |
| Ees (mmHg/ml) | 2.10±0.67 | 2.26±0.70 | <0.0001 |
| Eed (mmHg/ml) | 0.13±0.03 | 0.14±0.04 | <0.0001 |
| Ea/Ees | 0.69±0.15 | 0.62±0.14 | <0.0001 |
| Humoral factors | |||
| Glucose (mg/dl) | 97.52±19.92 | ||
| Insulin (µU/ml) | 4.8 (3.4–7.4) | ||
| HOMA2-IR | 0.60 (0.40–1.00) | ||
| Leptin (ng/ml) | 11.2 (6.1–19.2) | ||
| Adiponectin (ng/dl) | 8272 (5881–11191) |
From examinations 1 to 2, systolic, diastolic, and mean BPs decreased by 4.5±18.4, 4.1±10.3, and 4.3±11.3 mm Hg, respectively, while pulse pressure did not change (+0±14 mm Hg; p=0.4, Table 1). LV mass decreased, while chamber size and EF remained stable. Over 4 years, Ea decreased by 3%, while Ees and Eed increased on average by 14% and 8%, respectively (Table 1, Figure 1).
Figure 1. Arterial elastance (la), end-diastolic stiffness (1b), end-systolic stiffness (1c) and ventricular-arterial coupling ratio (Id) change over time by sex.
Data are expressed as estimated marginal mean and SEM. The influence of sex, time and their interaction was assessed.
Ea – arterial elastance; Eed – end-diastolic stiffness; Ees – end-systolic stiffness; Ea/Ees – ventricular-arterial coupling ratio
Longitudinal changes in arterial elastance
Arterial elastance was higher in women than in men at both examinations (p<0.001), but there was no difference in the slope of the age-related change in Ea between women and men (Figure 1A). None of the measures of central obesity at examination 1 or their changes over time were associated with the change in Ea, even after adjustment for weight loss (Table 2). After adjusting for age and sex, the magnitude of weight-change from examination 1 to 2 was associated with the change in Ea in both men and women (Table 2, Figure 2). BMI at examination 1 was negatively associated with Ea change in univariate analysis. However, baseline BMI was strongly associated with weight change (r= -0.78, p<0.001). After adjustment for weight change, BMI was no longer associated with Ea changes, while the association with weight change remained significant. Thus, the negative association between Ea change and BMI was driven by greater weight loss among heavier subjects.
Table 2. The association between obesity measures and arterial elastance (2a), end-systolic stiffness (2b), end-diastolic stiffness (2c) and ventricular-arterial coupling ratio (2d) changes over time. Bolded are statistically significant p values. Reported are slope coefficients with 95% confidence intervals.
| 2a Arterial elastance | ||||||
|---|---|---|---|---|---|---|
| All | Men | Women | ||||
| Beta Coefficient | p | Beta Coefficient | p | Beta Coefficient | P | |
| Waist (cm) | -0.001 (-0.002–0.0001) | 0.10 | -0.0001 (-0.002–0.002) | 0.89 | -0.001 (-0.003–0.001) | 0.19 |
| Waist-hip | -0.069 (-0.236–0.099) | 0.42 | -0.030 (-0.459–0.398) | 0.89 | 0.068 (-0.256–0.392) | 0.68 |
| Waist-height | -0.147 (-0.376–0.082) | 0.21 | 0.010 (-0.418–0.439) | 0.96 | -0.17 (-0.460–0.120) | 0.25 |
| Neck (cm) | -0.002 (-0.006–0.002) | 0.35 | 0.006 (-0.002–0.013) | 0.15 | -0.007 (-0.015–0.001) | 0.09 |
| Neck-height | -0.200 (-1.038–0.637) | 0.64 | 1.148 (-0.174–2.471) | 0.09 | -1.041 (-2.329–0.246) | 0.11 |
| BMI (kg/m2) | -0.004 (-0.007– -0.0001) | 0.026 | -0.001 (-0.007–0.005) | 0.66 | -0.005 (-0.009– -0.001) | 0.022 |
| Waist change (cm) | 0.0001 (-0.0001–0.001) | 0.57 | 0.0001 (-0.0001–0.001) | 0.48 | 0.0001 (-0.001–0.002) | 0.45 |
| Waist-hip change | 0.040 (-0.02–0.10) | 0.19 | 0.041 (-0.022–0.105) | 0.20 | 0.161 (-0.040–0.363) | 0.12 |
| Neck change (cm) | 0.0001 (-0.001–0.001) | 0.45 | -0.0001 (-0.001–0.001) | 0.89 | 0.001 (-0.0001–0.002) | 0.14 |
| Weight change (kg) | 0.001 (0.0001–0.002) | 0.003 | 0.002 (0.001–0.003) | 0.007 | 0.001 (-0.0001–0.002) | 0.15 |
| Weight change (%) | 0.512 (0.252–0.772) | <0.0001 | 0.543 (0.081–1.005) | 0.02 | 0.491 (0.177–0.804) | 0.002 |
| Date are adjusted for age and sex as appropriate | ||||||
| 2b End-systolic stiffness | ||||||
|---|---|---|---|---|---|---|
| All | Men | Women | ||||
| Beta Coefficient | p | Beta Coefficient | p | Beta Coefficient | p | |
| Waist (cm) | 0.002 (0.0001–0.003) | 0.11 | 0.001 (-0.002–0.003) | 0.59 | 0.003 (0.001–0.005) | 0.004 |
| Waist-hip | 0.191 (0.010–0.373) | 0.04 | -0.049 (-0.484–0.387) | 0.83 | 0.639 (0.271–1.006) | <0.001 |
| Waist-height | 0.436 (0.188–0.683) | <0.001 | -0.131 (-0.304–0.565) | 0.56 | 0.610 (0.281–0.939) | <0.001 |
| Neck (cm) | 0.005 (0.001–0.009) | 0.019 | 0.002 (-0.006–0.010) | 0.60 | 0.016 (0.007–0.025) | <0.001 |
| Neck-height | 1.687 (0.783–2.590) | <0.001 | 0.278 (-1.071–1.626) | 0.69 | 3.459 (2.007–4.911) | <0.001 |
| BMI (kg/m2) | 0.003 (-0.001–0.006) | 0.17 | -0.002 (-0.008–0.004) | 0.46 | 0.005 (0.0001–0.009) | 0.05 |
| Waist change (cm) | 0.0001 (-0.0001–0.001) | 0.55 | 0.0001 (-0.0001–0.001) | 0.48 | 0.0001 (-0.001–0.001) | 0.95 |
| Waist-hip change | 0.026 (-0.022–0.075) | 0.29 | 0.024 (-0.026–0.074) | 0.35 | 0.068 (-0.113–0.248) | 0.46 |
| Neck change (cm) | 0.0001 (-0.001–0.001) | 0.70 | 0.0001 (-0.001–0.001) | 0.84 | 0.001 (-0.001–0.001) | 0.79 |
| Weight change (kg) | 0.0001 (-0.0001–0.001) | 0.46 | 0.001 (-0.0001–0.002) | 0.035 | 0.001 (-0.001–0.002) | 0.35 |
| Weight change (%) | 0.204 (-0.490–0.082) | 0.16 | 0.231 (-0.241–0.704) | 0.34 | 0.207 (-0.158–0.571) | 0.27 |
| Date are adjusted for age, Ea change and sex as appropriate | ||||||
| 2c End-diastolic stiffness | ||||||
|---|---|---|---|---|---|---|
| All | Men | Women | ||||
| Beta Coefficienth | p | Beta Coefficient | p | Beta Coefficient | p | |
| Waist (cm) | -0.001 (-0.002–0.0001) | 0.06 | -0.001 (-0.003–0.002) | 0.6 | -0.002 (-0.003–0.0001) | 0.097 |
| Waist-hip | -0.001 (-0.174–0.172) | 0.99 | 0.194 (-0.257–0.645) | 0.4 | 0.123 (-0.206–0.452) | 0.46 |
| Waist-height | 0.093 (-0.334–0.148) | 0.45 | 0.022 (-0.462–0.506) | 0.93 | -0.104 (-0.401–0.192) | 0.49 |
| Neck (cm) | -0.001 (-0.006–0.003) | 0.56 | 0.002 (-0.006–0.011) | 0.59 | 0.002 (-0.011–0.006) | 0.56 |
| Neck-height | 0.565 (-0.341–1.471) | 0.22 | 0.958 (-0.591–2.507) | 0.23 | 0.720 (-0.574–2.014) | 0.28 |
| BMI (kg/m2) | -0.005 (-0.009– -0.002) | 0.002 | -0.006 (-0.012– -0.001) | 0.08 | -0.005 (-0.009– -0.001) | 0.001 |
| Waist change (cm) | 0.0001 (-0.0001–0.001) | 0.14 | 0.0001 (-0.0001–0.001) | 0.33 | 0.001 (-0.001–0.002) | 0.09 |
| Waist-hip change | 0.036 (-0.010–0.082) | 0.13 | 0.029 (-0.023–0.082) | 0.27 | 0.145 (-0.011–0.301) | 0.07 |
| Neck change (cm) | 0.0001 (-0.0001–0.001) | 0.41 | -0.0001 (-0.001–0.001) | 0.90 | 0.001 (-0.0001–0.002) | 0.10 |
| Weight change (kg) | 0.0001 (-0.001–0.0001) | 0.16 | 0.0001 (-0.0001–0.001) | 0.33 | 0.001 (-0.0001–0.002) | 0.09 |
| Weight change (%) | 0.689 (0.429–0.948) | <0.0001 | 0.901 (0.413–1.389) | <0.001 | 0.613 (0.305–0.922) | <0.001 |
| Date are adjusted for age, Ea change and sex as appropriate | ||||||
| 2d Ventricular-arterial coupling ratio | ||||||
|---|---|---|---|---|---|---|
| All | Men | Women | ||||
| Beta Coefficient | p | Beta Coefficient | p | Beta Coefficient | P | |
| Waist | -0.002 (-0.003– -0.0001) | 0.013 | -0.001 (-0.003–0.002) | 0.58 | -0.003 (-0.005– -0.001) | 0.002 |
| Waist-hip | -0.188 (-0.377–0.001) | 0.051 | 0.012 (-0.454–0.478) | 0.96 | -0.667 (-1.041– -0.292) | 0.0001 |
| Waist-height | -0.435 (-0.692– -0.177) | 0.001 | -0.088 (-0.553–0.378) | 0.71 | -0.654 (-0.988– -0.319) | 0.0001 |
| Neck | -0.004 (-0.009–0.0001) | 0.053 | -0.001 (-0.010–0.007) | 0.75 | -0.016 (-0.026– -0.007) | 0.001 |
| Neck-height | -1.448 (-2.392– -0.503) | 0.003 | 0.072 (-1.373–1.518) | 0.92 | -3.458 (-4.934– -1.981) | 0.0001 |
| BMI | -0.003 (-0.007–0.001) | 0.13 | 0.002 (-0.004–0.008) | 0.56 | -0.005 (-0.010– -0.001) | 0.03 |
| Waist change (cm) | 0.0001 (-0.0001–0.001) | 0.60 | 0.0001 (-0.001–0.001) | 0.76 | 0.0001 (-0.001–0.002) | 0.53 |
| Waist-hip change | 0.022 (-0.035–0.079) | 0.45 | 0.012 (-0.048–0.073) | 0.70 | 0.124 (-0.080–0.328) | 0.23 |
| Neck change (cm) | 0.0001 (-0.001–0.001) | 0.67 | 0.0001 (-0.001–0.001) | 0.95 | 0.0001 (-0.0001–0.001) | 0.60 |
| Weight change | 0.0001 (-0.0001–0.001) | 0.25 | 0.001 (-0.0001–0.002) | 0.052 | 0.0001 (-0.001–0.001) | 0.83 |
| Weight change % | 0.082 (-0.215–0.379) | 0.59 | 0.147 (-0.359–0.653) | 0.57 | 0.056 (-0.317–0.429) | 0.77 |
Data are adjusted for age and sex as appropriate
Figure 2. Arterial elastance at Exam 1 and Exam 2 (Panel A) and arterial elastance change between exams (Panel B) by weight change quartiles in women and men.
Data are adjusted for age and sex. *p<0.05 for the difference from Exam 1.
Ea – arterial elastance; ΔEa – arterial elastance change between exams
Longitudinal changes in end-diastolic elastance
As previously reported by our group, Eed was higher in women than in men at both examinations (p<0.001), the slope of Eed increase with aging was higher in women than in men (p=0.02; Figure 1B) and increasing body weight was directly correlated with increasing Eed in univariate analysis (r=0.25, p<0.0001). None of the measures of central obesity at examination 1 or their changes over time were associated with the change in Eed (Table 2). After adjusting for age and Ea change, weight gain remained positively associated with the age-related increase in Eed in both men and women (Figure 3).
Figure 3. End-diastolic stiffness at Exam 1 and Exam 2 (Panel A) and end-diastolic stiffness change between exams (Panel B) by weight change quartiles in women and men.
Data are adjusted for age, sex and arterial elastance change between exams. *p<0.05 for the difference from Exam 1.
Eed – end-diastolic stiffness; ΔEa – end-diastolic stiffness change between exams
Longitudinal changes in end-systolic elastance
Ees was higher in women than in men at both examinations (p<0.001), but there was no difference in the slope of age-related Ees increase between genders (p=0.57) (Figure 1C). As previously reported in this population, weight gain was associated with increase in Ees in univariate analysis (r=0.12, p<0.0001). However, after adjusting for age and changes in Ea, weight change was no longer correlated with change in Ees (Table 2). However, after adjusting for age and changes in Ea, measures of central obesity and neck circumference were positively associated with the age-related increase in Ees. Sex-stratified analysis revealed that the positive correlation between ventricular systolic stiffening and central obesity measures was driven exclusively by women and was absent in men (Table 2, Figure 4). As assessed by AIC, neck-to-height ratio showed the strongest association with ΔEes (AIC =-232.4), while there was only a small difference between waist-to-height (AIC =-210.7) and waist-to-hip ratios (AIC =-206.4). There was no correlation between changes in central obesity measures and changes in Ees.
Figure 4. A&B: End-systolic stiffness at Exam 1 and Exam 2 (Panel A) and end-systolic stiffness change between exams (Panel B) by neck-to-height quartiles at Exam 1 in women; C&D: End-systolic stiffness at Exam 1 and Exam 2 (Panel C) and end-systolic stiffness change between exams (Panel D) by insulin level quartiles at Exam 1 in women.
Data are adjusted for age and arterial elastance change between exams. *p<0.05 for the difference from Exam 1
Ees – end-systolic stiffness; ΔEa end-systolic stiffness change between exams
Longitudinal changes in ventricular-arterial coupling
Ventricular-arterial coupling ratio decreased in men and women with no difference in the slope of decrease (p=0.14, Figure 1D). Similar to observations with the change in Ees, changes in Ea/Ees were correlated with measures of central obesity in women but not in men (Table 2).
Humoral factors and ventricular-arterial coupling
Plasma levels of HDL cholesterol, total cholesterol, triglycerides, C-reactive protein, adiponectin and leptin at examination 1 were not associated Ea and Ees changes (Table 3). Insulin level, insulin resistance measured as HOMA2-IR and glucose level at examination 1 were positively associated with Ees increase in women but not men (Figure 4). Adjusting for measures of central obesity, including neck-to-height ratio and waist-to-height ratio, eliminated the significance of this association, while obesity measures remained associated with Ees change. We did not find any relationship between humoral factors and Eed.
Table 3. Association between biomarkers and arterial elastance (3a) and end-systolic elast ance (3b) change.
| 3a Arterial elastance | ||||||
|---|---|---|---|---|---|---|
| All | Men | Women | ||||
| Beta Coefficient | p | Beta Coefficient | p | Beta Coefficient | p | |
| Total cholesterol | -0.001 (-0.001–0.0001) | 0.80 | -0.0001 (-0.001–0.0001) | 0.19 | 0.0001 (-0.0001-0.001) | 0.59 |
| HDL cholesterol | 0.0001 (-0.001–0.001) | 0.89 | -0.001 (-0.003–0.001) | 0.24 | 0.0001 (-0.002-0.002) | 0.91 |
| Triglycerides | -0.013 (-0.087–0.062) | 0.74 | -0.030 (-0.133–0.073) | 0.57 | 0.010 (-0.099-0.19) | 0.86 |
| Glucose | 0.001 (-0.001–0.0001) | 0.42 | 0.001 (-0.001–0.001) | 0.70 | 0.001 (-0.002–0.001) | 0.59 |
| Insulin | -0.017 (-0.078–0.044) | 0.58 | -0.043 (-0.049–0.134) | 0.36 | -0.059 (-0.142-0.024) | 0.16 |
| HOMA2-IR | -0.030 (-0.078–0.042) | 0.55 | 0.041 (-0.048–0.131) | 0.37 | -0.060 (-0.142–0.021) | 0.15 |
| Adiponectin | -0.007 (-0.066–0.053) | 0.82 | -0.068 (-0.159–0.024) | 0.15 | 0.022 (-0.065-0.109) | 0.62 |
| Leptin | -0.013 (-0.035–0.062) | 0.59 | -0.024 (-0.065–0.113) | 0.60 | 0.034 (-0.45-0.112) | 0.40 |
| adjusted for age and sex as appropriate | ||||||
| 3b End-systolic stiffness | ||||||
|---|---|---|---|---|---|---|
| All | Men | Women | ||||
| Beta Coefficient | p | Beta Coefficient | p | Beta Coefficient | p | |
| Total cholesterol | -0.0001 (-0.001–0.0001) | 0.71 | -0.0001 (-0.001–0.0001) | 0.38 | 0.0001 (-0.001–0.001) | 0.63 |
| HDL cholesterol | -0.0001 (-0.001–0.001) | 0.68 | 0.001 (-0.001–0.003) | 0.55 | -0.001 (-0.002–0.001) | 0.53 |
| Triglycerides | 0.032 (-0.113–0.049) | 0.44 | 0.069 (-0.174–0.035) | 0.19 | 0.013 (-0.112–0.0.137) | 0.84 |
| Glucose | 0.001 (-0.001–0.001) | 0.59 | -0.001 (-0.002–0.0001) | 0.13 | 0.002 (0.0001–0.003) | 0.01 |
| Insulin | 0.056 (-0.010–0.122) | 0.1 | -0.040 (-0.133–0.053) | 0.4 | 0.130 (0.036–0.225) | 0.007 |
| HOMA2-IR | 0.058 (-0.007–0.123) | 0.08 | -0.046 (-0.137–0.045) | 0.32 | 0.141 (0.048–0.234) | 0.003 |
| Adiponectin | 0.026 (-0.091–0.040) | 0.44 | 0.012 (-0.105–0.082) | 0.8 | 0.028 (-0.128–0.073) | 0.59 |
| Leptin | 0.020 (-0.033–0.072) | 0.46 | 0.009 (-0.082–0.100) | 0.84 | 0.061 (-0.029–0.152) | 0.18 |
| Data are adjusted for age, ΔEa and sex as appropriate | ||||||
| 3c End-diastolic stiffness | ||||||
|---|---|---|---|---|---|---|
| All | Men | Women | ||||
| Beta Coefficient | p | Beta Coefficient | p | Beta Coefficient | p | |
| Total cholesterol | 0.0001 (-0.0001–0.001) | 0.48 | 0.0001 (-0.001–0.001) | 0.59 | 0.0001 (-0.001–0.001) | 0.69 |
| HDL cholesterol | 0.001 (-0.001–0.002) | 0.34 | 0.0001 (-0.002–0.002) | 0.87 | 0.001 (-0.001–0.002) | 0.46 |
| Triglycerides | 0.005 (-0.072–0.082) | 0.90 | -0.003 (-0.114–0.107) | 0.96 | 0.009 (-0.099–0.118) | 0.87 |
| Glucose | 0.0001 (-0.001–0.001) | 0.69 | 0.001 (-0.001–0.002) | 0.32 | -0.0001 (-0.002–0.001) | 0.59 |
| Insulin | -0.040 (-0.102–0.023) | 0.21 | -0.063 (-0.159–0.034) | 0.20 | -0.027 (-0.111–0.057) | 0.53 |
| HOMA2-IR | -0.035 (-0.096–0.027) | 0.27 | -0.055 (-0.150–0.040) | 0.25 | -0.024 (-0.107–0.059) | 0.57 |
| Adiponectin | 0.013 (-0.049–0.074) | 0.69 | -0.049 (-0.107–0.087) | 0.84 | 0.018 (-0.070–0.107) | 0.69 |
| Leptin | -0.019 (-0.068–0.031) | 0.46 | -0.037 (-0.134–0.060) | 0.46 | -0.066 (-0.146–0.013) | 0.10 |
Data are adjusted for age, ΔEa and sex as appropriate
Discussion
This is the first large-scale population-based study to comprehensively examine correlations between measures of central and general obesity, changes in obesity over time and longitudinal changes in ventricular and arterial stiffness in humans. We found that weight gain over 4 years was associated with significant increases in left ventricular diastolic stiffness in both men and women, while decreases in weight were associated with reductions in arterial load. Measures of central obesity and insulin resistance were associated with exaggerated increases in end-systolic elastance in women, but not in men, indicating that there are sex differences in the biology of age-related ventricular systolic stiffening. These findings suggest that strategies to enhance weight loss could mitigate or prevent age-related changes in ventricular structure and function that promote progression to HFpEF. In addition, the presence of central obesity in women may help identify a group of people at higher risk for developing incident HFpEF that might be targeted with preventive treatments.
Obesity is capable of producing hemodynamic alterations that predispose to changes in cardiac morphology and ventricular function (25) and is a potent independent risk factor for HF (26). Cross-sectional studies have shown that BMI or and central adiposity are associated with LV dysfunction and arterial stiffness (27). Russo et al (28) showed that higher BMI is associated with DD, while Ammar et al. found that waist-to-hip ratio was a stronger correlate than BMI (6). Canepa et al (29) recently observed that the correlation between central adiposity and DD was independent of general adiposity and was confined to women. However, cross-sectional studies do not provide an accurate picture of true age-related longitudinal changes.
We observed that weight gain was associated with significant increases in LV diastolic stiffness, despite reductions in blood pressure, LV mass and wall stress. This implies that diastolic LV stiffening does not result exclusively from hypertensive LV remodeling but is rather driven by weight gain even after accounting for afterload. These data extend upon studies of morbid obesity (30,31) where surgically-induced weight loss improved DD. Adiposity may impair diastolic function by limiting energetic availability (30) or increasing in myocardial lipid content (32), which is correlated with increased LV diastolic stiffness (33,34). While some studies have suggested that weight loss may increase mortality (35) or have no effect on CVD events (36), the current data support for the hypothesis that weight loss might mitigate or prevent increases in ventricular stiffness with aging.
Weight change was associated with the changes in Ea and Ees, but weight change was no longer predictive of Ees change after adjusting for Ea. This suggests that the effect of weight change on Ees might be mediated by its effects on afterload, but this hypothesis cannot be proven by these data. Increased neck circumference and central obesity was associated with greater increases in Ees in women. Increases in Ees are typical of normal aging but are greater in HFpEF. Elevated Ees has important implications for cardiovascular homeostasis, leading to greater blood pressure lability with load alteration, limited stroke volume reserve during exercise and increases in the metabolic cost to enhance cardiac output during stress (17, 37-39).
The correlation between central obesity and Ees progression was confined to women, suggesting an important sex difference in age-related ventricular stiffening. A similar finding was recently reported in a cross sectional study, where WC was associated with DD in women but not men (40). Intriguingly, Manrique et al observed that while insulin resistance develops in male and female mice exposed to the typical “Western” diet, only female animals developed LV DD, fibrosis and oxidative stress (41). These findings, also typical of human HFpEF, provide insight into the greater predilection for women to develop HFpEF compared to men (42) and are consistent with a recently proposed pathogenetic models in HFpEF (7).
Neck circumference, a proxy for upper-body fat, was a strong predictor of Ees progression. Increased neck circumference may lead to nocturnal airway obstruction, which is associated with both insulin resistance (43) and DD (44). Neck circumference is more closely related to visceral adiposity and insulin resistance than WC (23), and is more closely associated with metabolic disturbances than subcutaneous fat (12). Insulin level and resistance were not independently associated with Ees after accounting for abdominal adiposity or neck-height ratio. It is plausible that increases in neck circumference reflect enhanced ectopic fat accumulation associated with organ-specific fat depots, which have effects primarily on adjacent anatomic organs directly via lipotoxicity, or indirectly via cytokine secretion (45).
The ACC/AHA guidelines emphasize the progressive nature of HF from risk (Stage A), to asymptomatic structural disease (Stage B) to symptoms (Stages C-D) (46). Recent studies have shown that interventions guided by risk markers can reduce the risk for developing LV dysfunction and improve CVD outcomes (47). In this regard, central adiposity may be an important risk marker for “Stage B” HFpEF, allowing for identification of patients at highest risk to develop symptomatic (Stage C) HFpEF, who might benefit from preventive interventions.
Limitations
Echo-Doppler data inherently have greater variability compared with invasive measurements. Nearly half (614 or 44%) of subjects did not have adequate paired data for elastance measurement, and this group showed greater adiposity, introducing potential bias. In subjects with weight loss we do not know if this was intentional (“dieting”) or associated with chronic diseases (cachexia). BMI reflects both fat content and muscle mass (48), and weight change does not necessarily reflect changes in fatness (49), so relationships between absolute fat content and LV stiffness could not be addressed. Measurements of percent body fat as well as visceral and subcutaneous fat might provide additional insight. The study cohort was almost exclusively white, and these results may apply to other ethnic groups. We did not find any effect of changes in WC or waist-to-hip ratio on ventricular-arterial mechanics, and this may be related to the greater imprecision of tape measurements as compared to scale measurements. In mixed-effect models, we did not adjust for multiple comparisons, which may have led to false positive associations between obesity measures and parameters of ventricular-arterial coupling. However, we have verified these results by comparing differences between quartiles of obesity measures. This study did not relate measures of adiposity to clinical outcomes and future research is required to determine whether the correlations between adiposity and ventricular-arterial mechanics alter outcomes such as HF incidence or survival.
Conclusions
In men and women greater than or equal to 45 years of age, weight loss positively influences age-related changes in arterial elastance, while weight gain increases diastolic left ventricular stiffness, independent of changes in arterial load. Increased neck circumference and central obesity are associated with amplification of the age-related increase in left ventricular end-systolic stiffness in women but not men. These findings offer further insight into the greater predilection for women and for obese patients to develop HFpEF and they suggest that strategies to reduce body fat might be useful to slow age-related progression of left ventricular stiffness and reduce risk of developing HFpEF, particularly in women.
Supplementary Material
Acknowledgments
Funding Source: NHLBI- RO1- 55502, by the European Regional Development Fund, project FNUSA-ICRC (Z.1.05/1.1.00/02.0123) and Czech Ministry of Health (NT13434-4/2012).
Abbreviations
- BMI
body mass index
- BP
blood pressure
- CVD
cardiovascular disease
- DD
diastolic dysfunction
- Ea
effective arterial elastance
- Eed
end-diastolic elastance
- Ees
end-systolic elastance
- EF
ejection fraction
- ESP
end-systolic pressure
- HF
heart failure
- HFpEF
heart failure with preserved ejection fraction
- LV
left ventricular
- SV
stroke volume
- WC
waist circumference
Footnotes
Disclosures: We have no conflicts of interest to report.
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