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European Heart Journal Advance Access originally published online on January 19, 2008
European Heart Journal 2008 29(6):741-747; doi:10.1093/eurheartj/ehm605
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Left ventricular mass predicts heart failure not related to previous myocardial infarction: the Cardiovascular Health Study

Giovanni de Simone1,*, John S. Gottdiener2, Marcello Chinali1 and Mathew S. Maurer3

1 Department of Clinical and Experimental Medicine, Federico II University Hospital, via S.Pansini 5, 80131 Napoli, Italy
2 University of Maryland Hospital, Baltimore, MD, USA
3 Columbia University, New York, NY, USA

Received 28 June 2007; revised 3 December 2007; accepted 6 December 2007; online publish-ahead-of-print 19 January 2008.

* Corresponding author. Tel: +39 81 746 2013, Fax: +39 81 546 6152, Email: simogi{at}unina.it

See page 698 for the editorial comment on this article (doi:10.1093/eurheartj/ehn031)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Aims: The relationship of left ventricular hypertrophy (LVH) to incident heart failure (HF) not attributable to myocardial infarction (MI) has not been defined. We assessed whether LVH is an independent predictor of MI-independent HF.

Methods and results: LVH was assessed by echocardiographic LV mass index (in g/m2.7) and excess of LV mass (eLVM, in % of the observed value) relative to the amount predicted by sex, stroke work, and height, using a prognostically validated equation in 2078 participants of Cardiovascular Health Study without prevalent MI and normal systolic function. Increasing eLVM was associated with progressively increasing left atrial dimension and concentric geometry, decreasing systolic (P < 0.0001), and diastolic function (P < 0.04). After adjustment for age, sex, obesity, diabetes, hypertension, and antihypertensive therapy, and accounting for by incident MI, hazard of HF increased by 1% for each 1% increase in eLVM and by 3% for each g/m2.7 increase in LV mass index (both P < 0.0001). The results were confirmed when also C-reactive protein and measures of systolic (endocardial shortening) and diastolic function (categories of E/A ratio) were added to the Cox models.

Conclusion: In an elderly population, LVH, measured as LV mass index or eLVM is an independent predictor of incident HF not related to prevalent or incident MI.

Key Words: Left ventricular hypertrophy • Echocardiography • Heart failure • Follow-up • Cardiovascular outcome • Excessive left ventricular mass • Population study


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
Among the clinical presentations of cardiovascular (CV) disease attributable to CV risk factors and their combination, heart failure (HF) has a substantial relevance, due to the increasing incidence, which is related to both the reduced mortality for myocardial infarction (MI) and the aging of population.1 The aging issue is particularly relevant because development of HF is different if the background disease is MI (with near constant systolic dysfunction) or other non-ischaemic conditions (arterial hypertension, obesity, diabetes, etc.),1,2 more likely to be present in elderly populations not previously exposed to MI. There is, at present, little information on patterns of risk of HF in individuals without MI or idiopathic dilated cardiomyopathy,1 and on other phenotypic characteristics favouring its progression in the absence of coronary heart disease. Integrating information of CV risk factor profile with markers of preclinical CV disease,3 such as left ventricular (LV) mass might help stratifying risk of HF from the lowest to the highest degrees of severity.

To evaluate the presence of LV hypertrophy (LVH), in addition to the direct estimation of LV mass normalized for body size (LV mass index), we have also proposed using the excess of LV mass relative to the amount appropriate for individual cardiac workload, sex, and body size,4 as an attempt to better graduate risk associated with traditionally defined LVH.5 In fact, this excess of LV mass progressively identifies high CV risk independent of clear-cut LVH.6,7 Excess LV mass is associated with a cluster of geometric and functional abnormalities, including concentric LV geometry, reduced LV chamber function, depressed midwall shortening, and prolonged LV relaxation, which suggests that the excess of LV mass might portend impending HF.8

Based on the above elements, we have analysed the cohort of the Cardiovascular Health Study to assess whether LV mass index and the excess of LV mass predict incident HF, in the absence of more direct causes attributable to initial LV systolic dysfunction or prevalent MI and independent of CV risk factors and other potential confounders.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 References
 
The Cardiovascular Health Study (CHS) is a population-based study including participants aged 65–100 years from four Field Centers: Forsyth County, NC; Sacramento County, CA; Allegheny County, PA; and Washington County, MD. The majority of participants formed the ‘initial cohort’, whereas an additional group of about 700 participants (mostly African-Americans) was recruited 3 years later as a ‘new minority cohort’. The overall design, objectives, and recruitment strategy of CHS, and characteristics of the recruited cohorts have been previously presented in detail.9,10 For the purpose of the present analysis, we studied a selected CHS population (n = 2078) from both original and minority cohorts, with available M-mode echocardiographic examination at year 7 of the study,11 which for the purpose of this study was considered as the baseline. The selection criteria were adopted to exclude participants with technically inadequate echocardiographic examination and to minimize prevalence of individual characteristics potentially correlated with subsequent HF. Thus, the following subjects were excluded:

  1. participants with unreadable M-mode echocardiograms (n = 1095);
  2. participants with prevalent MI, atrial fibrillation, or HF (n = 690);
  3. participants with suboptimal evaluation of wall motion (n = 174);
  4. participants with qualitative evaluation of mild, moderate, or severe LV dysfunction (n = 190);11
  5. participants with LV endocardial shortening <25% (n = 41).

Definition of co-morbidities
Hypertension was defined according to JNC VII guidelines,12 as blood pressure ≥140/90 mmHg or presence of antihypertensive treatment, consistent with previous CHS reports.9,10 Impaired fasting glucose (≥110 mg/dL) and diabetes (>125 mg/dL or antidiabetic therapy) were defined according to American Diabetes Association13 Overweight and obesity were defined according to NIH 1998 guidelines.14

Laboratory
C-reactive protein was measured as previously reported15 and considered as a continuous variable in multivariate analysis as a potential independent predictor of HF.

Outcome events
During the semi-annual contacts, participants were asked about occurrence of diagnosed HF in the past 6 months. If HF was reported, medical records were reviewed by the HF Events Subcommittee for final adjudication. Details on the criteria for adjudication have been previously reported.16 HF was adjudicated when the constellation of symptoms and physical signs were present together with a diagnosis of HF from a physician and on going consistent treatment, as previously reported in detail.17 The time of last contact before ascertainment of HF ranged between 32 and 144 months. Last contact for the present study was taken on year 2000.

Echocardiography protocol and measurements
Baseline echocardiograms for the present analysis were considered those performed between 1994 and 1995, at year 7 of the study and including the minority recruitment cohort. The design of the echocardiography protocol used in CHS has been previously described in detail.18 Briefly, each subject underwent an echocardiogram that was recorded on super-VHS tapes using a standardized protocol. All measurements were made at a Core Echocardiography Reading Center from digitized images using an off-line image analysis system equipped with customized computer algorithms.11,19

Two-dimensionally targeted M-mode measurements of end-diastolic inter-ventricular septal thickness, LV internal dimension (LVIDd), LV posterior wall thickness, and left atrial dimension were measured according to the recommendations of the American Society of Echocardiography.20 LV mass was calculated from a necropsy-validated formula21 and normalized for body height in metres to the power 2.7.22 LV relative wall thickness was calculated as the ratio of LV mean wall thickness to LV internal radius (1/2 LVIDd) and normalized to an age of 46 years, as previously suggested.23 Systolic function was assessed at the chamber and midwall levels by computing respective systolic shortenings.24 Transmitral peak E/A velocity ratio was used as a raw estimate of LV filling characteristics.

Definition of excess of left ventricular mass
LV mass was evaluated as the deviation from the value predicted individually from haemodynamic load, body size, and sex, as previously reported.7 Haemodynamic load was assessed by computing stroke work (SW), estimated as systolic blood pressure times Teichholz-derived25 stroke volume and converted to gram-metres (g-m) by multiplying by 0.0144. Height in metres raised to the power of 2.7 was used as the measure of body size.22 The values of ideal LV mass for the individual SW, gender, and body size were estimated using a multiple linear equation developed in a reference normal population,22 which has been prognostically validated in population different from the training one:6,26


Formula

where sex was assigned the value of 1 for men and 2 for women.

By this equation, the measured echocardiographic LV mass could be expressed as the deviation (excess) from the predicted value (observed/predicted). For convenience, the ratio between observed and predicted LV mass will be called ‘excess of LV mass’ and expressed as % of predicted.

Statistical analysis
Data were analysed using SPSS 12.0 software (SPSS, Chicago, IL) and expressed as mean±one standard deviation. For convenience, the population sample was divided into quartiles of both LV mass index and excess of LV mass. Descriptive statistics were obtained using {chi}2 distributions (with Monte Carlo method for computation of exact two-tailed P-value,when appropriate) and analysis of covariance. Trend among quartiles was studied using linear or quadratic polynomial contrast and type III sum of squares. C-reactive protein was log10 transformed due to skewed distribution.

Log-cumulative hazard functions were computed by Cox regression analysis for the two main predictors: LV mass index or excess of LV mass. Proportional hazard assumption has been verified by plotting residuals of Cox regression of LV mass index or excess of LV mass vs. time to occurrence of HF in the uncensored observations and verifying the independence of both variables from time (r2 was 0.008 and 0.00001, respectively). Due to possible cause–effect relationship with incident HF, incident MI was censored as a competing risk event in the Cox model. Cox regression was programmed hierarchically by entering covariates (age, sex, obesity, diabetes, hypertension, antihypertensive treatment) and forcing LV mass index or excess of LV mass into the model, thereafter (model 1). In a second model (model 2) also C-reactive protein was considered among primary covariates. A third Cox model (model 3) was generated, using the same design as earlier, to assess how much other echocardiographic parameters add to the prediction from model 2. For model 3, same covariates as model 2 were entered in the first order block, with the addition of LV mass index or excess of LV mass, relative wall thickness, endocardial shortening, left atrial dimension, and transmitral Doppler peak E/A ratio entered in the subordinate block. The transmitral Doppler peak E/A ratio was categorized in three subsets due to its J-shaped risk distribution, according to previously reported partition values (<0.6, between 0.6 and 1.5—set as the normal—and >1.5).27 The null hypothesis was rejected at a two-tailed P-value of ≤0.05. The model building procedures of Cox models presented in this analysis have been validated for consistency with alternative models forcing all variables of interest and showing near-identical results.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
Hypertension was present in 59% of participants. Prevalence of hypertension was 46, 59, 59, and 71% from the lowest to the highest quartile of LV mass index (P < 0.0001), whereas it tended to decrease with increasing quartiles of excess of LV mass (66, 62, 53, and 56%, respectively; P = 0.0001).

Prevalence of obesity was 8, 15, 19, and 36% from the lowest to the highest quartile of LV mass index, and 12, 18, 18, and 29% with increasing quartiles of excess of LV mass (both P < 0.0001).

Increasing prevalence of diabetes was associated with increasing quartile of LV mass index (9, 11, 12, 15%, respectively; P = 0.02) but not with excess of LV mass (12, 10, 11, 14%, respectively; P = 0.389).

Table 1 shows demographic characteristics and risk profile of quartiles of excess of LV mass, adjusting for the presence of arterial hypertension. Age, sex distribution, heart rate, and plasma creatinine were similar among quartiles. BMI significantly increased and blood pressure decreased with increasing excess of LV mass (all P < 0.0001). Increased average value of excess of LV mass was also significantly associated with progressively higher values of C-reactive protein and lower values of HDL-cholesterol (all P < 0.005). LDL-cholesterol did not differ among quartiles of excess of LV mass.


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  		Table 1 Baseline general characteristics of the study population, in relation to quartiles of excess of left ventricular mass

 
Baseline echocardiographic characteristics
LV and left atrial dimensions increased significantly from the lowest to the highest quartile of excess of LV mass (both P < 0.0001) (Table 2). Increasing level of excess of LV mass was also associated with progressively increasing relative wall thickness (raw or age-normalized values), and progressively decreasing endocardial and midwall shortening. In particular, from the lowest to the highest quartile of excess of LV mass, endocardial shortening decreased by 15% and midwall shortening by 25% (both P < 0.0001), whereas wall stress increased by no more than 5%. Table 2 also shows that transmitral peak E/A velocity ratio decreased with increase in excess of LV mass (p = 0.005).


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  		Table 2 Left ventricular geometry and function of the study population, in relation to quartiles of excess of left ventricular mass

 
Characteristics of incident HF
During follow-up (10 ± 2 years), new HF occurred in 216 participants (8%), 77 of whom (36%) also had acute MI (n = 147) during the follow-up. Incidence of HF among participants with incident MI was 52%, as opposed to the incidence of 5% in those without incident MI (OR = 14.18; 95% CI = 9.83–20.47; P < 0.0001).

Adjusting for age, sex, obesity, diabetes, arterial hypertension, antihypertensive treatment and accounting for by incident MI as a competing risk event, the hazard for incident HF increased by 3% at each g/m2.7 increase in LV mass index (HR = 1.03, 95% CI: 1.02–1.04; P < 0.0001). Similarly, adjusting for covariates and accounting for by incident MI, hazard for incident HF increased by 1% at each 1% increase in excess of LV mass (HR = 1.01; 95% CI: 1.01–1.02; p < 0.0001).

C-reactive protein was added as a covariate to the above models, without modification of the impact of LV mass index (Table 3, model A) and excess of LV mass (Table 3, model B).


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  		Table 3 Incident heart failure in relation to left ventricular mass index or excess left ventricular mass, adjusting for age, sex, obesity, arterial hypertension diabetes antihypertensive treatment and log10 C-reactive protein, accounting for by incident myocardial infarction as a competing risk event

 
Finally, Table 4 shows that increasing left atrial dimension and decreasing endocardial shortening added to the predictive models with either LV mass index or excess LV mass, whereas E/A ratio classification (P = 0.87) and relative wall thickness (P = 0.45) did not. In this final model, risk of HF was higher in men than in women, increased with aging and C-reactive protein and was predicted by higher LV mass and left atrial dimension, and lower endocardial shortening.


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  		Table 4 Additional significant predictors of incident heart failure independent of covariates, measures of left ventricular hypertrophy and competing risk events

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
The incidence of HF is high and is related to age, male gender, coronary heart disease, higher blood pressure, inflammation, and other circulating factors,15,28,29 and is often associated with preserved LV systolic chamber function, especially in women and in elderly subjects.15,30 Although the ability to predict incident HF appears in the CHS cohort, as well as in other populations,31 significantly related to the presence of coronary heart disease, the prevalence of HF with normal systolic function in this cohort suggests that a number of HF events are not related to coronary heart disease.31,32 The normal baseline systolic function, in the absence of prevalent MI, does not allow quantifying the risk of incident HF, in the studied elderly participants of the CHS cohort. Although there is evidence that occurrence of HF with normal systolic function is substantially due to diastolic dysfunction,33 identification of features preceding HF in the absence of coronary heart disease remains a difficult task.

Thus, our study extends previous data,15 by analysing LV mass index and excess of LV mass in CHS participants free of prevalent coronary heart disease and with initially normal LV systolic function. In the present analysis, evaluation of LV hypertrophy has been done using a traditional LV mass index and the excess of LV mass relative to sustaining cardiac workload, which we have recently proposed as a bioassay to capture clusters of LV geometric abnormalities and both systolic and diastolic dysfunction.8 Both indices of LV hypertrophy were potent predictors of incident HF, independently of major CV risk factors and inflammatory status. This relation was not influenced by the few cases of incident MI, considered as a competing risk event in the analysis. Despite the different distributions, also highlighted in the present study,5 no advantage could be identified in using calculation of excess of LV mass when compared with the simpler LV mass index.

The available data permit cautious speculations about why LV hypertrophy is associated with impending HF also in the absence of MI. In the elderly population of the CHS, systolic function is in general normal,15,34 or even supra-normal, in some subset, as shown in Table 2. The key feature of the geometric–functional abnormality appears to be echocardiographic increase in myocardial relative wall thickness, very evident across quartiles of excess LV mass (but also confirmed among quartiles of LV mass index—results not shown). Development of LV concentric geometry tends in fact to preserve pump function despite depressed intrinsic wall mechanics,24,35,36 through both direct mechanisms related to the organization of myocardial fibres35 and geometric modifications maintaining myocardial afterload near normal.37 Especially at the highest degrees of LV hypertrophy, represented by the highest quartile of excess of LV mass or of LV mass index, in this study, as well as in other populations,5,26,38,39 the most severe concentric LV geometry is also associated with systolic dysfunction not only at the midwall, but also at the chamber level, suggesting that under a certain level of impaired myocardial contractility, this geometric adaptation cannot anymore fully preserve LV chamber function. Thus, at the highest level, concentric remodelling fails to preserve LV chamber function despite the favourable effect on end-systolic wall stress.40 In addition, diastolic dysfunction is also associated with excessive increase in LV mass, characterized by coexisting prolonged relaxation and features of increased myocardial stiffness (not evaluated in the present study).41 These geometric and functional features suggest that myocardial structure is progressively altered with increasing severity of LV hypertrophy and that the increase in LV mass is not necessarily due to real muscle hypertrophy, while fibrosis component is increasingly greater and correlates with the degree of diastolic dysfunction.42 Although an extensive analysis of diastolic dysfunction has not been done, the presence of increasing left atrial diameter in the final predictive model shown in Table 4 strongly suggests chronic, severe abnormality of LV filling properties.43 This model of prediction also shows that even within the range of normality, LV systolic chamber function is an important factor for incident HF, and confirms that the predictive power of LV hypertrophy is also independent of LV chamber function.

Although there is no direct evidence, several indirect findings tend to sustain this hypothesis and suggest new lines of research. There is evidence that pressure overload concentric hypertrophy is more associated with myocardial fibrosis than volume overload in both experimental and human studies.44–46 Wong et al.47 measured the acoustic density of myocardium (a marker of fibrosis) in overweight–obese subjects, in the absence of overt heart disease, and demonstrated abnormalities consistent with myocardial fibrosis. Although blood pressure was the same as normal weight controls, the overweight and obese subjects had concentric LV geometry, and presumably similar stroke volume (as suggested by similarity in LV diastolic dimensions and ejection fraction), thus indicating a substantial excess of LV mass in relation to their cardiac workload. High degree of LV hypertrophy with an excess of LV mass over 114% of the predicted for individual workload, as suggested by our findings, might, therefore, indicate myocardial structural changes heralding subsequent HF, independently of prevalent, as well as incident myocardial infraction.

Limitations
This, as well as other study populations, can be influenced by selection bias. However, given that this study population is epidemiologically selected from a free-living population of elderly individuals, it likely has reasonable generalizability for aged populations. Since most patients who present with HF are elderly, the study, therefore, has clinical relevance, though whether these findings may be extrapolated to younger individuals remains to be determined.

Conclusions
LV hypertrophy is a potent, independent predictor of incident HF in a coronary heart disease-free elderly population, and helps explain the occurrence of HF, independently of prevalent and incident MI and systolic dysfunction.

Conflict of interest: none declared.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
This work was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 

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