Abstract
Background
People over the age of 85 are the world's most rapidly growing age group. Ejection fraction (EF) may be limited prognostically in this population and myocardial contraction fraction (MCF) may be more accurate. The objective of this longitudinal study was to assess the prognosis of MCF in an age-homogenous, community-dwelling population of subjects.
Methods
Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed with a portable echocardiograph at the subjects place of residence. Standard echocardiographic assessment of cardiac structure and function including MCF was performed. Values of EF and MCF above and below the median for males and females were defined as normal and abnormal in categorical analysis. 5-year mortality was assessed via a centralized government database.
Results
418 subjects (199 males, 219 females) were enrolled in the study of whom 113 (27 %) died at the time of 5-year follow-up. Subjects who died had significantly lower MCF (32 ± 14 % vs 36 ± 12 %; p < 0.004) and EF (51.6 ± 11.6 % vs 56.3 ± 9.4 %; p < 0.0001) than survivors. The association between MCF and mortality remained significant on clinical multivariate analysis as both a categorical and continuous variable while EF was only significant as a continous variable. When both EF and MCF were added to the model only MCF as a categorical variable remained significant.
Conclusions
MCF assessed by home echocardiography provides additional prognostic information to EF and may be a superior predictor of 5-year mortality in a community-dwelling population of the oldest old.
Keywords: Elderly, Echocardiography, Ventricular function
1. Background
People over the age of 85 (the “oldest old”) are the world's most rapidly growing age group [1]. The aging of the population is an increasing challenge for cardiovascular care given the relatively high frequency of cardiac death in this population [2]. Previous studies that have utilized echocardiography in elderly patients to examine prognosis included a broad range of ages with relatively few patients over the age of 80 [3], [4], [5]. In addition, existing studies of echocardiography in the “oldest old' have been performed in the hospital or clinic setting, contributing to a biased study population in this elderly age group as subjects may have difficulty in leaving their homes [6].
Left ventricular ejection fraction (EF) is the most commonly used echocardiographic measurement of LV systolic function. EF is a volumteric assessment which is dependant on loading conditions and which may not accurately assess systolic function in the setting of left ventricular hypertrophy and heart failure with preserved ejection fraction, findings common in the elderly population [7], [8], [9]. Myocardial contraction fraction (MCF) is defined as the ratio of LV stroke volume (SV) to myocardial volume and may more accurately assess LV systolic function than EF particularly in the setting of LVH and/or HFPEF [10], [11], [12]. The aim of this longitudinal study was to examine the association between MCF and 5-year mortality in a age-homogenous, community-dwelling population of 85–6 year olds.
2. Methods
2.1. Participants
Subjects were recruited from the Jerusalem Longitudinal Cohort Study that was initiated in 1990 and has followed an age homogenous representative cohort of West Jerusalem residents born between June 1920 and May 1921. The methodology has been described elsewhere in detail [13], [14]. The present study examines data from the third phase of data collection, which took place during 2005/2006. Subjects were interviewed and examined in their homes on two separate occasions, each session requiring the completion of a structured interview that lasted about an hour and a half. Information was collected from socioeoconomic, demographic, medical, functional, cultural and cognitive domains. The institutional ethics committee of the Hadassah Hebrew University Medical Center approved the study design, and written informed consent was obtained from all participants.
2.2. Sampling
Subjects identified from the electoral register were randomly chosen from the total sample of people born 1920–21 and living in Jerusalem in 2005. As reported previously, we performed an examination of death certificates and hospital admission records three years following the initiation of the study compared the study group to other subjects of the sample frame in Jerusalem who either refused or were not invited to enroll in the cohort study [13], [14]. Subjects of the study group, those who declined to participate and those baseline cohort members not enrolled had near identical mortality and disease specific hospital morbidity, thus demonstrating the representative nature of the initial study group in comparison to the total same age stratum of the Jerusalem population. Echocardiography was performed in randomly selected subjects in a convenience sample by neighborhood, evenly distributed between new recruits and subjects participating from previous phases. No significant differences in medical diagnoses were noted between the members of the cohort who underwent echocardiography compared to those who did not. (Supplementary Table 1) Participiants who underwent echocardiography were slightly more physically active with better functional status. Survival status at 5 year follow-up was assessed via the centralized Ministry of Interior database. Follow-up was available for all study subjects.
3. Measures
3.1. Cardiovascular
Diagnosis of ischemic heart disease (IHD) was based on a history of hospitalization for myocardial infarction (MI), or an acute coronary syndrome, coronary catheterization with evidence of a significant coronary artery disease, or previous coronary artery bypass grafting surgery. Hypertension was assessed by the examining study physician and defined as treatment with antihypertensive medications or subjects' self-reporting. Blood pressure was measured with the participant in a sitting position three times with a use of a validated electronic sphygmomanometer (Omron 705IT; Omron Corporation, Kyoto, Japan) and the results were averaged. Hyperlipidemia was defined as use of cholesterol-lowering medications. Diabetes mellitus was a composite of hypoglycemic medications, personal history or a medical record diagnosis. Congestive heart failure (CHF) and the presence of renal disease was based on hospital discharge diagnosis and according to examining research physician diagnosis at the time of examination at home. Body mass index was calculated and dichotomized to low (≤25) and high (>25). A cognitive assessment was performed according to a standardized Mini Mental State Examination with cognitive impairment defined as ≤ 24/30. Physically active was defined as at least 4 h a week self reported physical activity.
3.2. Echocardiography
Subjects had standard 2-D and Doppler echocardiography at their place of residence with a portable echocardiograph (Vivid I, GE Healthcare, Haifa, Israel). All subjects underwent 2-D and Doppler echocardiography with m-mode measurements of the interventricular septum, posterior wall, and left ventricular (LV) end-systolic and end-diastolic diameters according to the recommendations of the European Association of Echocardiography/American Society of Echocardiography [15]. Measurements were performed offline by an experienced echocardiographer (DL) for three consecutive cardiac cycles and averaged. Subject height and weight at the time of the study were recorded and body surface area calculated. LV mass was calculated according to a necropsy validated formula of LV mass (grams) = 0.8 X (1.04 X ((septal thickness + LV internal diameter + posterior wall thickness)3 – (LV internal diameter)3)) + 0.6 and indexed to body surface area [16]. Given the high prevalence of basal septal hypertrophy in this population, septal thickness measurements were taken below the level of the basal septum. Left atrial volumes were calculated at end-systole from the apical 4-chamber view using the area-length method and indexed to body surface area [17].
Ejection fraction (EF) was calculated by averaging measurements of end-diastolic and end-systolic volumes from the apical 4 and 2 chambers view using biplane Simpsons method for three consecutive beats. In patients with atrial fibrillation, measurements were averaged for 5 consecutive beats. Subjects with inadequate imaging of the endocardial surface in apical views were excluded. Normal systolic function was defined as ejection fraction ≥ 52 % in men and ≥ 54 % in women [14]. Myocardial contraction fraction was calculated as the ratio of LV stroke volume to myocardial volume × 100. Myocardial volume was defined as calculated LV mass/mean density of myocardium where the accepted value of myocardial tissue density is 1.055 g/ml. As normal values for MCF in this population are not well defined, values of EF and MCF above and below the median for males and females were defined as normal and abnormal in categorical analysis.
Diastolic parameters were measured from the apical 4-chamber view using pulsed-wave Doppler at the level of the mitral leaflet tips and tissue Doppler imaging of the septal and lateral myocardial walls and included early (E) and late (A) transmitral flow velocities and the ratio of early to late velocities (E/A). Early (e') and late (a') diastolic mitral annular tissue velocities at both the septum and lateral walls were obtained and the ratio of E/e' using the average of septal and lateral tissue velocities obtained was calculated as an index of diastolic function [18].
3.3. Data analysis
Descriptive statistics were performed and as the cardiac parameter data was normally distributed, results are described as means and standard deviations. Percentages were calculated as appropriate. For continuous variables differences between means were calculated using t-tests and Chi-square test for proportions. Cumulative survival was assessed by Kaplan-Meier analysis and log rank test for statistical significance. Adjusted and unadjusted Cox proportional hazard models were performed for the variables of MCF and EF analyzed by tertiles. Adjusted clinical variables were selected based on p < 0.15 in the univariate analysis. Sensitivity analysis was performed analyzing the groups by median values as well as excluding participants with EF < 40 % (n = 36). Receiver operating curves were generated using both EF and MCF as variables for predicting mortality. All p values were 2-tailed and p < 0.05 was considered significant. The data storage and analysis was performed using R 3.4.3.
4. Results
A total of 526 participants underwent echocardiography and were included in the study. 418 subjects of whom 219 were female and 199 male had technically acceptable echocardiograms which enabled accurate calculations of both EF and MCF. (Fig. 1) A total of 113 subjects (27 %) died at 5 year follow-up. Demographic and clinical characteristics of the study population as a whole is depicted in Table 1. Survivors were significantly more physically active and had significantly less dementia, ischemic heart disease, diabetes, chronic kidney disease and congestive heart failure.
Fig. 1.
Participant flow chart.
Table 1.
Clinical characteristics of the study population.
| Criterion | Total 100 % (n = 418) |
|
| Gender | Female | 52.4 % (2 1 9) |
| Education | < 12 years | 49.6 % (2 0 6) |
| BMI | Low High |
33.2 % (1 3 0) 24 % (94) |
| Physically active | Yes | 68.2 % (2 8 1) |
| ADL dependency | Yes | 29.1 % (1 1 8) |
| Dementia | Yes | 16.6 % (66) |
| Hypertension | Yes | 69.6 % (2 9 1) |
| Blood pressure (mmHg) | Systolic Diastolic |
146.3 ± 20.6 73.9 ± 10.5 |
| Ischemic heart disease | Yes | 37.6 % (1 5 7) |
| Diabetes mellitus | Yes | 22 % (92) |
| Chronic renal disease | Yes | 9.6 % (40) |
Echocardiographic measurements of the study population are presented in Table 2. Subjects who died had significantly lower MCF (32 ± 14 % vs 36 ± 12 %; p < 0.004) ad EF (51.6 ± 11.6 % vs 56.3 ± 9.4 %; p < 0.0001) than survivors. In addition, non survivors had significantly lower indices of LV volumes, LA volumes and LV mass index (LVMI) than surivivors.
Table 2.
Echocardiographic parameters in the study population.
| Total |
Did not Die |
Died |
P-value | ||||
|---|---|---|---|---|---|---|---|
| Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | ||
| EF (%) | 55 (10.2) | 56.2 (50.7–61.7) | 56.30 (9.39) |
56.99 (51.72,61.76) |
51.64 (11.61) |
54.11 (43.33,60.24) |
0.0001 |
| MCF (%) | 0.35 (02.1) | 0.34 (0.27–0.42) | 0.36 (0.12) |
0.35 (0.29,0.43) |
0.32 (0.14) |
0.29 (0.21,0.37) |
0.0040 |
| E:e' | 12.2 (4.8) | 11.3 (9.2–14.1) | 11.74 (4.32) |
11.13 (8.90,13.33) |
13.42 (5.82) |
12.57 (9.67,15.97) |
0.0160 |
|
LV S wave (cm/s) |
7.7 (2.1) | 7.7 (6.2–9) | 7.79 (1.95) |
7.90 (6.37,8.92) |
7.55 (2.45) |
7.10 (5.70,8.95) |
0.3600 |
|
LVESVI (ml/m2) |
31.7 (14.5) | 28.7 (22.1–37.3) | 29.92 (12.33) |
28.17 (21.75,35.54) |
36.59 (18.39) |
32.47 (23.09,45.23) |
0.0009 |
|
LVMI (g/m2) |
121.7 (35.3) | 117.4 (97–139.8) | 116.98 (29.94) |
113.11 (95.94,133.00) |
136.04 (45.58) |
133.88 (112.24,155.83) |
0.0004 |
|
LVEDVI (ml/m2) |
68.7 (18.5) | 66.8 (56.3–79.2) | 67.29 (16.46) |
66.40 (56.32,76.40) |
72.69 (22.84) |
70.80 (57.38,86.25) |
0.0310 |
|
LAVI (ml/m2) |
38.4 (14.6) | 35.9 (29.1–45) | 36.50 (13.60) |
34.68 (28.66,42.98) |
43.55 (16.16) |
42.83 (30.49,52.07) |
0.0002 |
EF = ejection fraction.
MCF = myocardial contraction fraction.
LVESVI = left ventricular end-systolic volume index.
LVEDVI = left ventricular end-diastolic volume index.
LVMI = left ventricular mass index.
When parameters were dichotomized, a significantly higher percentage of non-survivors had MCF below the median for the population (63.7 vs 36.3 %; p 0.0008). A significantly higher percentage of non-survivors had EF below the median as well (60.2 % vs 39.8.5 %; p 0.008). When the population was divided into 4 catgories according to normal/abnormal EF and MCF, 111 subjects had both low EF and low MCF. This group had significantly worse survival than the other groups.
Kaplan-Meier curves by tertiles are presented in Fig. 2. For males, tertiles of MCF were < 29 %, 29–40 % and > 40 % and of EF were < 51 %, 51–58 % and > 58 %. For females, tertiles of MCF were < 29 %, 29–38 % and > 38 % and of EF were < 54 %, 54–61 % and > 61 % Both EF and MCF were predictive of mortality. Receiver operating curves are presented in Fig. 3. The area under the curve for MCF was 0.63 while for EF it was 0.61, this difference did not reach statistical significance. When ROC analysis was repeated including only subjects with preserved EF, the results remained not statistically significant.
Fig. 2.
Kaplan-Meier analysis of mortality of EF and MCF by tertiles demonstrating significantly reduced survival in the lowest tertile of both EF and MCF.
Fig. 3.
ROC of EF and MCF with no significant difference in the AUC between EF and MCF.
Table 3 depicts the multivariate adjusted Cox proportional hazard models for both MCF and EF examined as tertiles. The lowest tertile of MCF was significantly associated with increased mortality. EF by tertiles was no longer significantly associated with mortality.
Table 3.
Multivariate model for mortality (Cox proportional hazard) according to tertiles.
|
Categorical |
||||
|---|---|---|---|---|
| HR | (95 %CI) | P-value | ||
| MCF | MCF- lowest tertile | 2.34 | (1.4, 3.92) | 0.0012 |
| MCF- middle tertile | 1.68 | (0.96, 2.94) | 0.0708 | |
| Sex | 1.35 | (0.89, 2.06) | 0.1555 | |
| Education < 12 years | 0.73 | (0.47, 1.12) | 0.1525 | |
| Dementia | 1 | (0.59, 1.69) | 0.9997 | |
| Reduced ADL | 3.35 | (2.04, 5.5) | <0.0001 | |
| Ischemic heart disease | 1.6 | (1.07, 2.4) | 0.0234 | |
| Diabetes | 1.24 | (0.77, 2.01) | 0.3704 | |
| Chronic renal disease | 1.93 | (1.08, 3.45) | 0.0258 | |
| Physical activity | 0.72 | (0.44, 1.18) | 0.1914 | |
| EF | EF- lowest tertile | 1.46 | (0.85, 2.51) | 0.1745 |
| EF- middle tertile | 1.38 | (0.81, 2.37) | 0.2394 | |
| Sex | 1.34 | (0.89, 2.04) | 0.1632 | |
| Education < 12 years | 0.77 | (0.5, 1.19) | 0.2354 | |
| Dementia | 1.11 | (0.65, 1.87) | 0.7091 | |
| Reduced ADL | 3.4 | (2.07, 5.56) | <0.0001 | |
| Ischemic heart disease | 1.54 | (1.01, 2.33) | 0.0427 | |
| Diabetes | 1.17 | (0.72, 1.9) | 0.5346 | |
| Chronic renal disease | 1.99 | (1.11, 3.58) | 0.0213 | |
| Physical activity | 0.8 | (0.49, 1.31) | 0.3729 | |
Table 4 depicts the multivariate adjusted Cox proportional hazard models for both MCF and EF examined independently as continuous as well as categorical variables. Both MCF and EF were significantly associated with mortality as continuous variables while only MCF was significant categorically. In addition, increased functional disability, and the presence of ischemic heart disease and chronic kidney disease were associated with mortality in the multivariate model. When EF and MCF were examined in the same model, only MCF as a categorical variable remained significantly associated with mortality. The Cox hazard models were repeated after excluding 36 participants with EF < 40 % and EF was no longer significantly associated with mortality while the association with MCF remained significant.
Table 4.
Multivariate model for mortality (Cox proportional hazard).
|
I. Only MCF (per unit as continuous, above median as categorical): | ||||||
|---|---|---|---|---|---|---|
|
Continuous |
Categorical |
|||||
| HR | (95 %CI) | P-value | HR | (95 %CI) | P-value | |
| MCF (%) | 0.08 | (0.01, 0.46) | 0.0046 | 0.58 | (0.38, 0.87) | 0.009 |
| Gender | 1.38 | (0.91, 2.09) | 0.1299 | 1.36 | (0.9, 2.06) | 0.15 |
| High Education | 0.74 | (0.48, 1.15) | 0.1774 | 0.72 | (0.47, 1.1) | 0.1286 |
| Dementia | 1.04 | (0.61, 1.75) | 0.8951 | 1.02 | (0.61, 1.72) | 0.9336 |
| Problem in ADL | 3.45 | (2.12, 5.62) | <0.0001 | 3.44 | (2.11, 5.61) | <0.0001 |
| Ischemic HD | 1.57 | (1.05, 2.35) | 0.0294 | 1.62 | (1.08, 2.42) | 0.0185 |
| Diabetes | 1.17 | (0.73, 1.89) | 0.5093 | 1.16 | (0.72, 1.88) | 0.5388 |
| Kidney Disease | 1.93 | (1.08, 3.43) | 0.0258 | 1.91 | (1.07, 3.42) | 0.0292 |
| Physically Active | 0.77 | (0.47, 1.25) | 0.2887 | 0.78 | (0.48, 1.28) | 0.3271 |
| II. Only EF(per unit as continuous, above median as categorical):: | ||||||
|---|---|---|---|---|---|---|
| Continuous |
Categorical |
|||||
| HR | (95%CI) | P-value | HR | (95%CI) | P-value | |
| EF (%) | 0.97 | (0.95, 0.99) | 0.0028 | 0.75 | (0.49, 1.14) | 0.1751 |
| Gender | 1.2 | (0.79, 1.83) | 0.3928 | 1.34 | (0.89, 2.03) | 0.1664 |
| High Education | 0.77 | (0.5, 1.19) | 0.2418 | 0.76 | (0.49, 1.18) | 0.2202 |
| Dementia | 1.18 | (0.7, 2.02) | 0.5328 | 1.09 | (0.64, 1.84) | 0.7529 |
| Problem in ADL | 3.19 | (1.96, 5.2) | <0.0001 | 3.48 | (2.14, 5.66) | <0.0001 |
| Ischemic HD | 1.34 | (0.87, 2.06) | 0.19 | 1.55 | (1.02, 2.34) | 0.039 |
| Diabetes | 1.11 | (0.69, 1.8) | 0.6723 | 1.14 | (0.7, 1.86) | 0.5905 |
| Kidney Disease | 2.12 | (1.18, 3.81) | 0.012 | 1.93 | (1.08, 3.46) | 0.0277 |
| Physically Active | 0.77 | (0.47, 1.25) | 0.2937 | 0.81 | (0.5, 1.33) | 0.4074 |
|
III. Multivariate analysis including both EF and MCF as tertiles | |||
|---|---|---|---|
| HR | (95%CI) | P-value | |
| EF- low tertile | 1.22 | (0.75, 1.99) | 0.4279 |
| EF- middle tertile | 1.01 | (0.56, 1.84) | 0.9701 |
| MCF- low tertile | 2.43 | (1.37, 4.28) | 0.0022 |
| MCF- middle tertile | 1.66 | (0.94, 2.93) | 0.0815 |
| Gender- Male | 1.36 | (0.89, 2.06) | 0.1526 |
| Education< 12 years | 0.74 | (0.48, 1.14) | 0.169 |
| Dementia | 1.00 | (0.59, 1.70) | 0.9994 |
| Reduced ADL | 3.34 | (2.02, 5.52) | <0.0001 |
| Ischemic Heart Disease | 1.61 | (1.06, 2.45) | 0.0264 |
| Diabetes | 1.26 | (0.78, 2.03) | 0.3519 |
| Chronic Renal Disease | 1.96 | (1.09, 3.51) | 0.0238 |
| Physical activity | 0.72 | (0.44, 1.18) | 0.1954 |
5. Discussion
Our study is the first to our knowledge to demonstrate the prognostic value of MCF in a community-dwelling population of the oldest old. The association between MCF and mortality remained after correction for possible confounders, is additive to EF and may be more significant than the prognostic value of EF, the standard echocardiographic measurment of LV systolic function.
Several previous studies have examined the prognostic value of LV systolic function as assessed by echocardiography in a elderly, community-dwelling population. In the Cardiovascular Health Study, a community-based study which enrolled patients over the age of 65, abnormal EF was found to be a significant, independent predictor of 5-year mortality, a finding consistent with our results [3]. We have previously demonstrated in our study cohort of 85–6 year olds that EF was predictive of mortality [19]. EF is a strictly volumetric technique that does not reflect actual myocardial shortening and is very sensitive to loading conditions and changes in LV geometry. In particular, changes in LV geometry assciated with aging such as increased wall thickness make assessment of systolic function by EF challenging in this age group [11], [20], [21]. The oldest old have a high prevalence of HFPEF and EF may not discern subtle abnormalities in systolic function in this age group [22], [23]. In addition, the elderly appear to have a relatively high prevalence of cardiac amyloidosis and MCF has been shown to be more accurate than EF in assessing systolic function in this population [24]. Therefore, indices of systolic function which are measures of myocardial shortening such as MCF or strain imaging may provide more accurate assessment of prognosis than EF in this increasingly large age group. Unlike strain, MCF does not require specialized software and is less dependent on technical factors such as frame rate. It synthesizes values of shortening in all domains and provides a numerical value roughly similar to EF which may be more familiar to clinicians [25].
MCF calculated by echocardiography has been shown to be associated with prognosis in the elderly. In a report from the Cardiovascular Health Study in subjects with normal EF over the age of 65, MCF was associated with all cause mortality [26]. A small study in elderly (mean age 82 years) patients with severe aortic stenosis undergoing TAVI showed that MCF < 30 % was significantly associated with mortality [27]. Our study confirms these findings, compares them to EF and expands them to an older community-based population with less bias given that the echo studies were performed at the subjects home. In our study, MCF appeared to be more significantly and consistently associated with survival than EF, particularly when analyzed as a categorical variable.
The major strengths of our study are the use of an age-homogenous cohort to minimize variability of the clinical findings and the use of home echocardiography. Previous studies using echocardiography in the oldest old population examined subjects in the hospital setting introducing significant bias. Studying patients at home ensures a more representative sample of this age group particularly when evaluating issues such as functional impairment given that dependent patients are presumably less likely to participate in studies outside the home.
The major limitation is the use of echocardiography in a subset of the total cohort, however this was a random subgroup and there were no significant differences in demographics such as gender, diabetes, hypertension and ischemic heart disease between the subjects who underwent echocardiography and those who did not so that the chance of selection bias is minimal. In addition, we do not have information regarding causes of mortality of incidence of cardiovascular events. There was a 13 % incidence of mitral annular calcification in this elderly cohort which may have affected tissue Doppler annular measurements. Strain measurements were not available at the time the study was performed.
In conclusion, our results show that echocardiographically determined MCF provides additional prognostic information to EF and may be a superior predictor of 5-year mortality in a community-dwelling population of the oldest old.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijcha.2022.101158.
Appendix A. Supplementary material
The following are the Supplementary data to this article:
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