Left ventricular hypertrophy (LVH) is an independent predictor of heart failure [1–7] and a reduced left ventricular (LV) ejection fraction . LVH may therefore determine the progression to heart failure with a reduced rather than preserved ejection fraction [9,10]. However, an increased LV mass (LVM) [11–13] or on-treatment decreases in LVM  have also been associated with an unchanged ejection fraction. In addition, LVH may even be associated with an enhanced ejection fraction for that predicted by wall stress  and on-treatment decreases in LVM have been related to an attenuation of rather than enhancement of indices of LV systolic chamber function . One explanation for the variable relationships between LVM or LVM indexed to height2.7 (LVMI) and LV systolic chamber function [11–16] is that absolute LVM and LVMI may incorporate a component of LVH considered to be compensatory in nature, while also reflecting a component of LVH that contributes to systolic decompensation of the LV chamber. The factors that determine whether LVH is a decompensatory response are nevertheless uncertain.
One proposal for the transition from compensated LVH to LV systolic chamber decompensation is that LVH in-keeping with work load [i.e. stroke work = blood pressure (BP) × stroke volume] is compensatory, while that exceeding workload [i.e. ‘inappropriate’ LVM [LVMinappr)]  contributes toward decompensation. Indeed, a number of studies have demonstrated an inverse relationship between LVMinappr and LV systolic chamber function [18–24]. However, whether LVMinappr is associated with a reduced systolic chamber function independent of and more strongly than absolute or indexed LVM is uncertain. Some prior studies conducted in select clinical samples have demonstrated inverse correlations between LV systolic chamber function and both absolute LVM as well as LVMinappr[18,19] and in one of these studies LVM was equally as strongly inversely correlated with ejection fraction as LVMinappr. This finding is at odds with the notion that it is only LVM beyond stroke work that explains decompensation. Thus, whether inverse relationships between LVMinappr and ejection fraction are independent of absolute LVM is unclear. In the present study conducted in a randomly selected community sample of black African ancestry with a high prevalence of inappropriate LVH, we therefore aimed to evaluate whether LVMinappr is inversely associated with ejection fraction independent of and more strongly than LVM or LVMI.
The present study was conducted according to the principles outlined in the Helsinki declaration. The Committee for Research on Human Subjects of the University of the Witwatersrand approved the protocol (approval numbers: M02–04–72 renewed as M07–04–69). Participants gave informed, written consent. The study design has previously been described [25–27]. Nuclear families of black African descent with siblings older than 16 years were randomly recruited from the South–West Township of Johannesburg, South Africa. Of the 1191 participants recruited, in a substudy consisting of 678 participants, 626 had all echocardiographic data required for the present analysis, and of these 437 had 24-h ambulatory BP measurements that met with prespecified quality-control criteria  (longer than 20 h and more than 10 and five readings for the computation of day and night means, respectively).
Clinical, demographic and anthropometric measurements
Demographic and clinical data were obtained using a standardized questionnaire [25–27]. Height and weight were measured using standard approaches and participants were identified as being overweight if their BMI was at least 25 kg/m2 and obese if their BMI was at least 30 kg/m2. Standard laboratory blood tests of renal function, liver function, blood glucose, lipid profiles, haematological parameters, and percentage glycated haemoglobin (HbA1c) (Roche Diagnostics, Mannheim, Germany) were performed. Diabetes mellitus or abnormal blood glucose control was defined as the use of insulin or oral hypoglycaemic agents or an HbA1c value greater than 6.1% . Menopause was confirmed with measurements of follicle stimulating hormone concentrations.
BP measurements were obtained by a trained nurse-technician using a standard mercury sphygmomanometer and using SpaceLabs monitors (model 90207) (ambulatory 24-h, day and night BP) as previously described .
Echocardiography was performed as previously described [25,26,29]. All measurements were recorded and analyzed off-line by experienced investigators who were unaware of the clinical data of the participants. LVM was determined using a standard formula  and indexed (LVMI) to height2.7. LV mean wall thickness was calculated as the mean of septal + posterior wall thickness. An LVMI more than 51 g/m2.7 was considered to be increased . Left ventricular ejection fraction (biplane Simpson) and midwall fractional shortening (FSmid) were calculated to determine LV pump and myocardial systolic function respectively using standard formulae . An ejection fraction of less than 55% was considered to be a reduced ejection fraction. A threshold of 55% was supported by identifying the lower 5% confidence interval for ejection fraction (55.8%) in 140 participants from the community-based study without clinically significant disease and normal clinical blood parameters who were normotensive, nondiabetic, and had a BMI less than 30 kg/m2. Stroke volume was evaluated from the difference between LV end-diastolic and systolic volumes determined using both the Teichholz  and the Z-derived  methods. Circumferential LV systolic wall stress was calculated as previously described .
The extent of inappropriate LVM (LVMinappr) was determined from predicted LVM as described by others , in which predicted LVM was calculated as 55.37 + (6.64 × height2.7) + [0.64 × (SBP × stroke volume × 0.014)] − (18.07 × sex), in which male sex = 1 and female sex = 2, and in which stroke volume was calculated from LV volumes assessed from the Z-derived method . Inappropriate LVM was expressed either as actual-predicted LVM in grams, or percent actual LVM/predicted LVM. An LVMIinappr more than 150% was considered to be increased. This threshold was identified from the upper 95% confidence interval for LVMIinappr determined in the same 140 participants employed to define thresholds for ejection fraction. In these participants the upper 95% confidence for LVMI was 51.8 g/m2.7. To ensure that the calculation for LVMinappr was suitable for the community studied, we determined whether the strong correlations between LVM or LVMI and stroke work were eliminated if LVM was expressed as LVMinappr.
Database management and statistical analyses were performed with SAS software, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA). Continuous data are reported as mean ± SD or mean ± SEM. Unadjusted means and proportions were compared by the large-sample z-test and the χ2-statistic, respectively. Independent relations between LVM, LVMI or LVMinappr and LV function were assessed from multivariate linear regression analysis with appropriate adjustors. Z-Statistics were used to compare correlation coefficients. Probability values were further adjusted for nonindependence of family members using the method of maximum likelihood as implemented by the mixed procedure as defined in the SAS package.
The demographic and clinical characteristics of those with and without echocardiographic data were similar (Table 1). A high proportion of participants were obese (Table 1). Of the 43% of participants that were hypertensive, only 36% had controlled BP. 18.5% of participants had inappropriate increases in LVM (LVMIinappr>150%) and 21.7% of participants had LVH (LVMI>51 g/m2.7). In the treated hypertensives 85.7% of participants were receiving low-dose hydrochlorothiazide, 15.7% calcium channel blockers, 21.1% angiotensin-converting enzyme inhibitors (ACEI) and 2.0% β adrenergic receptor blockers (β-blockers). None of the participants were receiving angiotensin receptor antagonists (ARB) or aldosterone receptor antagonists.
Suitability of the inappropriate LVM calculation
In contrast to strong positive correlations noted between LVM (or LVMI) and stroke work (r = 0.60–0.67, P < 0.0001), when LVM was expressed as LVMinappr, relations with stroke work were eliminated (r = −0.02, P = 0.67).
Clinical and demographic factors associated with inappropriate left ventricular mass or left ventricular mass indexed to height2.7
Participants with an increased LVMinappr or LVMI were older; consisted of more women; had a greater BMI and waist circumference; had more diabetes mellitus or an uncontrolled blood glucose; and more were receiving antihypertensive therapy (Table 2). Participants with an increased LVMinappr also had a higher pulse rate, but fewer smoked and consumed alcohol regularly (Table 2). Participants with an increased LVMI, but not those with an increased LVMinappr had an increased conventional (Table 2), and 24-h, day and night BP (data not shown). However, LV systolic wall stress was similar between the groups (Table 2).
Left ventricular structure and systolic function in participants with an increased inappropriate left ventricular mass or left ventricular mass indexed to height2.7
Participants with an increased LVMI and LVMinappr had an increased LVM, LVMI, LV mean wall thickness and LV end-diastolic diameter as compared to participants with a normal LVMI and LVMinappr (Table 3). Either with adjustments for confounders or unadjusted, LV ejection fraction and FSmid were decreased in participants with an increased LVMinappr (Table 3). In contrast, both LV ejection fraction and FSmid were similar in participants with as opposed to without an increased LVMI (Table 3). Secondary data analysis with adjustments for the use of ACEIs or β-blockers in place of ‘treatment for hypertension’ produced essentially the same differences in LV ejection fraction and FSmid between the groups (Supplemental Table S1, https://links.lww.com/HJH/A204).
Relationship between left ventricular mass, left ventricular mass indexed to height2.7, or inappriopriate left ventricular mass and ejection fraction or midwall fractional shortening
On bivariate and multivariate regression analysis with LV systolic wall stress and other confounders included as adjustors; LVMinappr was strongly and inversely associated with ejection fraction and FSmid (Table 4). In contrast, LVM and LVMI showed only a trend for an inverse association with ejection fraction and only after adjustments for confounders (Table 4). Neither LVM, nor LVMI were associated with FSmid (Table 4).
The relationships between LVMinappr and ejection fraction or FSmid were significantly stronger than the relationships between LVM or LVMI and ejection fraction or FSmid (Table 4) (P < 0.0001 for comparison of partial r values). Moreover, the relationships between LVMinappr and ejection fraction or FSmid remained unchanged despite further adjustments for LVM or LVMI (Table 4). The relationships between LVMinappr and ejection fraction also remained unchanged despite further adjustments for stroke volume (partial r = −0.43, confidence intervals = −0.49 to −0.37, P < 0.0001) or LV end-diastolic diameter (partial r = −0.47, confidence intervals = −0.53 to −0.40, P < 0.0001). Replacing LV systolic wall stress with conventional, 24-h, day, or night SBP showed similar relationships (data not shown).
Secondary data analysis with adjustments for the use of ACEIs or β-blockers in place of ‘treatment for hypertension’ produced essentially the same relationships (Supplemental Table S2, https://links.lww.com/HJH/A204).
Relative impact of left ventricular mass, left ventricular mass indexed to height2.7, or inappropriate left ventricular mass on ejection fraction and the odds of a reduced ejection fraction at a community level
With a number of factors included in a multivariate regression model, LVMinappr was second only to LV systolic wall stress in contributing to EF at a community level, whereas LVM and LVMI contributed little (Table 5). In the community studied, 44 of 626 participants (7%) had an ejection fraction less than 55%. With adjustments for age, sex, LV systolic stress, HbA1c, pulse rate, treatment for hypertension, regular smoking, regular alcohol intake and waist circumference, an increased LVMinappr was strongly associated with an odds of a reduced ejection fraction (<55%) (odds ratio = 6.85, confidence interval = 2.99–15.68, P<0.0001). In contrast, an increased LVMI was not associated with an odds of a reduced ejection fraction (odds ratio = 1.32, confidence interval = 0.60–2.92, P = 0.50).
The main findings of the present study are as follows: in a randomly selected community sample of black African ancestry, in contrast to a modest or a lack of relationship noted between LVM or LVMI and ejection fraction, an increased LVMinappr was strongly and independently related to a decreased ejection fraction even with adjustments for LVM or LVMI. Moreover, the strength of the relationship between LVMinappr and ejection fraction was greater than that of the relations between LVM or LVMI and ejection fraction. In a multivariate model with all potential determinants of EF included in the model, LVMinappr was second only to LV systolic wall stress in contributing toward ejection fraction at a community level and was a strong independent predictor of a reduced ejection fraction.
To-date whether inverse relationships exist between LVMinappr and LV systolic chamber function beyond that of absolute or indexed LVM is uncertain. In previous studies reporting on such relations [18–24] only in the Losartan Intervention For Endpoint Reduction (LIFE) study did the authors compare the relationships between LV systolic chamber function and either LVMinappr or LVM . In this regard, they noted that LVM was equally as strongly related to ejection fraction as LVMinappr, but they did not evaluate whether the LVMinappr-ejection fraction relationship persisted with adjustments for LVM or LVMI . However, the LIFE study consisted of a select patient group in that only participants with electrocardiographic evidence of LVH were recruited. Thus, mean LVM values in either the group of patients with increased or normal LVMinappr were markedly higher (227–271 g) in the LIFE  than in the present (145–202 g) study. In addition, mean LV systolic myocardial function (FSmid) values were lower in the LIFE (13.7–16.5%)  as compared to the present (20.9–23.5%) study. The LIFE study may therefore have selected for a group of participants with marked LVH and a higher risk of LV systolic dysfunction. Under these circumstances, relationships between absolute LVM and ejection fraction may have been more robust and difficult to distinguish from those between LVMinappr and ejection fraction. Irrespective of the reasons for the apparent discrepancy between the LIFE  and the present study, the present study provides clear evidence that LVMinappr is inversely related to ejection fraction beyond LVM or LVMI and hence supports the notion that LVH is a compensatory response to workload, but when exceeding that predicted by workload, is associated with LV systolic chamber decompensation.
Although a number of studies have demonstrated inverse relations between LVMinappr and LV systolic chamber function [18–24], in some prior studies [35–37] the existence of these relationships is less clear. In two prior studies [35,36], although ejection fraction was reduced in hypertensives without LVH but with an increased LVMinappr, EF was not reported as being correlated with LVMinappr. Moreover, in an alternative study  although LV systolic chamber function was markedly reduced in patients with an increased LVMinappr, in a multivariate model LV systolic chamber function was not reported as being independently correlated with LVMinappr. In contrast to the apparently inconsistent relations between LVMinappr and systolic chamber function [18–24,35–37], stress-corrected FSmid, a measure of LV systolic myocardial function, has nevertheless consistently been shown to be inversely related to LVMinappr[18–24,35–37]. It is therefore possible that under certain circumstances, although LVM in excess of that predicted by stroke work is associated with a reduced systolic myocardial function, the hypertrophy is in-part compensatory in nature in that it contributes toward maintaining LV chamber function in the face of deteriorating myocardial function. Only prospective studies evaluating the evolution of systolic functional changes in the transition from appropriate to inappropriate LVH and subsequent LV systolic chamber dysfunction will answer this question.
In studies in which inverse LVMinappr-LV systolic chamber function relations have previously been demonstrated [18–24], the authors have not adjusted for wall stress (afterload), the principal determinant of LV systolic function, or other determinants of LV systolic function, such as heart rate. Indeed, a reduced ejection fraction has been reported in patients with an increased LVMinappr who were also noted to have an increased LV wall stress . As indicated in the present study, LV systolic wall stress is the major determinant of ejection fraction at a community level. An increased wall stress could thus explain previously reported decreases in ejection fraction [18–24], at least in patients with an increased LVMinappr. In contrast, in the present study we show clear inverse relations between LVMinappr and ejection fraction independent of LV wall stress, conventional and ambulatory BP, and alternative confounders such as heart rate.
The potential clinical implications of the present study warrant consideration. Pending validation of the present results in prospective, intervention studies and with heart failure with a reduced ejection fraction as an outcome, the results of the present study suggest that LVMinappr may complement the use of LVMI when risk predicting or when assessing LVH regression with therapy. Future prospective studies evaluating the impact of regression of increases in LVMinappr independent of absolute LVM or LVMI on the development of heart failure with a reduced ejection fraction are therefore required.
The limitations of the present study are as follows: The present study was a cross-sectional study and hence does not allow us to draw conclusions regarding cause and effect. Thus, the inverse LVMinappr-ejection fraction relationships could be attributed to compensatory increases in LVM following LV systolic dysfunction rather than vice versa, or to residual confounding effects. However, recent evidence demonstrating that decreases in LVMinappr with antihypertensive therapy are strongly related to on-treatment increases in ejection fraction beyond changes in LVM and LVMI suggests that LVMinappr may indeed cause a decrease in EF . Second, the present study was conducted in one ethnic group (black African descent) with a high prevalence of LVMinappr and with higher thresholds for an increased LVMinappr determined in a healthy sample, than that previously reported on in other ethnic groups. However, the thresholds for LVMinappr corresponded to thresholds of LVMI of 51.8 g/m2.7 in the healthy sample, an accepted threshold for LVMI in this ethnic group . Third, we determined LVMinappr using predicted LVM values calculated from a formula derived in an alternative population . However, in support of the suitability of the calculation of LVMinappr in the community studied, in contrast to strong positive correlations noted between LVM (or LVMI) and stroke work, when LVM was expressed as LVMinappr, no residual relations with stroke work were observed.
In conclusion, in the present study we show that in a community sample of black African ancestry, LVM in excess of that predicted by LV work load (LVMinappr) is strongly and inversely related to ejection fraction independent of and more strongly than LVM or LVMI. These data therefore support the view that LVH, as indexed by LVM or LVMI incorporates a component of LVH that can be viewed as a compensatory change that preserves ejection fraction, but when this exceeds that predicted by LV workload, this excess in LV growth is associated with a decrease in ejection fraction.
This study was supported by the Medical Research Council of South Africa, the University Research Council of the University of the Witwatersrand, the National Research Foundation (Women in Research and the Thuthuka Program), the Circulatory Disorders Research Trust, and the Carnegie Programme. This study would not have been possible without the voluntary collaboration of the participants and the excellent technical assistance of Mthuthuzeli Kiviet, Nomonde Molebatsi, and Nkele Maseko.
Conflicts of interest
There are no conflicts of interest.
Reviewers’ Summary Evaluations Reviewer 1
Inappropriate left ventricular mass (LVM) was inversely related with ejection fraction (EF). This relation persisted after adjustment for LVM and other confounders. The implications are that when the degree of left ventricular hypertrophy exceeds that predicted by workload, it becomes associated with systolic dysfunction. The results of this study are partly confirmatory of previous studies. Novelties are: 1) the demonstration that the inverse relation between inappropriate LVM and EF is independent of absolute LVM; 2) the study has not been conducted in a selected cohort of patients, but in a random population, albeit of black African ancestry.
This study shows that an inappropriate left ventricular mass is independently and inversely related to ejection fraction. The relation is closer than for left ventricular workload, and when exceeding the predicted workload this is associated with left ventricular systolic decompensation. The study is based on a large number of subjects; as they were of black African descent the results may not be generalized to other populations.
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