Both, left ventricular (LV) hypertrophy and remodeled LV geometry predict future cardiovascular events. There is also some evidence that the pattern of LV hypertrophy might refine this predictive value. This study analyzed baseline echo images obtained at enrollment in the VALIANT study. Increased baseline LV mass and abnormal LV geometry, in patients with LV dysfunction, heart failure, or both after a myocardial infarction (MI), was a powerful predictor of future cardiovascular events. This study confirms that the pattern of LV remodeling, obtained with simple imaging just after an MI, contains important prognostic information for future events. The study also demonstrated that the pattern of LV hypertrophy carried the greatest risk of such adverse events. These insights are further discussed by Dr. Konstam in an accompanying editorial comment.
Objectives This study sought to understand prognostic implications of increased baseline left ventricular (LV) mass and geometric patterns in a high risk acute myocardial infarction.
Background The LV hypertrophy and alterations in LV geometry are associated with an increased risk of adverse cardiovascular events.
Methods Quantitative echocardiographic analyses were performed at baseline in 603 patients from the VALIANT (VALsartan In Acute myocardial iNfarcTion) echocardiographic study. The left ventricular mass index (LVMi) and relative wall thickness (RWT) were calculated. Patients were classified into 4 mutually exclusive groups based on RWT and LVMi as follows: normal geometry (normal LVMi and normal RWT), concentric remodeling (normal LVMi and increased RWT), eccentric hypertrophy (increased LVMi and normal RWT), and concentric hypertrophy (increased LVMi and increased RWT). Cox proportional hazards models were used to evaluate the relationships among LVMi, RWT, LV geometry, and clinical outcomes.
Results Mean LVMi and RWT were 98.8 ± 28.4 g/m2 and 0.38 ± 0.08. The risk of death or the composite end point of death from cardiovascular causes, reinfarction, heart failure, stroke, or resuscitation after cardiac arrest was lowest for patients with normal geometry, and increased with concentric remodeling (hazard ratio [HR]: 3.0; 95% confidence interval [CI]: 1.9 to 4.9), eccentric hypertrophy (HR: 3.1; 95% CI: 1.9 to 4.8), and concentric hypertrophy (HR: 5.4; 95% CI: 3.4 to 8.5), after adjusting for baseline covariates. Also, baseline LVMi and RWT were associated with increased mortality and nonfatal cardiovascular outcomes (HR: 1.22 per 10 g/m2 increase in LVMi; 95% CI: 1.20 to 1.30; p < 0.001) (HR: 1.60 per 0.1-U increase in RWT; 95% CI: 1.30 to 1.90; p < 0.001). Increased risk associated with RWT was independent of LVMi.
Conclusions Increased baseline LV mass and abnormal LV geometry portend an increased risk for morbidity and mortality following high-risk myocardial infarction. Concentric LV hypertrophy carries the greatest risk of adverse cardiovascular events including death. Higher RWT was associated with an increased risk of cardiovascular complications after high-risk myocardial infarction.
Increased left ventricular (LV) mass and LV hypertrophy are independent predictors of cardiovascular morbidity and mortality irrespective of etiology (1–3). The risk of death or nonfatal complications is increased 2- to 4-fold in the presence of LV hypertrophy in patients with hypertension, coronary artery disease, or uncomplicated myocardial infarction (MI) (1). The prevalence of LV hypertrophy is closely associated with advancing age and severity of hypertension, ranging from 6% in persons <30 years of age to 43% in those >69 years (4) and from 20% to 50% in populations with mild-to-severe hypertension (1,4).
The LV adaptation to arterial hypertension can result in different LV geometric responses, and further classification of hypertensive patients by their ventricular geometry may provide incremental value beyond ventricular mass for further cardiovascular risk stratification (5–9). Hypertensive patients with concentric LV hypertrophy have the highest incidence of cardiovascular events including death (9).
Despite the association of LV hypertrophy with prognosis in patients with hypertension, uncertainty still persists with regard to the independent prognostic value of LV geometric patterns (10,11). In addition, the independent contribution of LV geometry, relative wall thickness (RWT), and LV mass to prognosis have not been well characterized in a high-risk post-MI population. To explore the prognostic value of LV mass and geometry in high-risk MI, we studied patients enrolled in the echocardiographic substudy of the VALIANT (VALsartan In Acute myocardial iNfarcTion) trial.
The VALIANT trial was designed to test the hypothesis that the angiotensin receptor blocker valsartan, either alone or in combination with the proven angiotensin-converting enzyme inhibitor captopril, would be superior or not inferior to a proven dose of captopril in reducing cardiovascular morbidity or mortality after MI (12). A total of 14,703 patients with heart failure, LV systolic dysfunction (ejection fraction [EF] ≤35% on echocardiography or ≤40% on contrast angiography), or both were enrolled within 12 h to 10 days after acute MI (12). The median duration of follow-up was 24.7 months. Patients were randomly assigned in a 1:1:1 ratio to treatment with either captopril (target dose 50 mg 3 times daily), valsartan (target dose 160 mg twice daily), or the combination of valsartan and captopril (target doses of 50 mg 3 times daily and 80 mg twice daily) (12). Clinical sites participating in the main VALIANT study were invited to enroll patients in the VALIANT echocardiographic study, and patients enrolled in the VALIANT trial at these sites were eligible for inclusion in the VALIANT echocardiographic study. Entry criteria were identical to those for the main VALIANT study. Patients were included regardless of infarct location or ST-segment characteristics. A total of 610 patients from the total VALIANT population (N = 14,703) were enrolled in the echocardiographic substudy and underwent baseline 2-dimensional echocardiography at a mean time of 5.0 ± 2.5 days following the index MI (13). A total of 94 clinical sites in 13 countries participated in the VALIANT echocardiographic substudy. The details of patient characteristics have been previously described (13) and the inclusion and exclusion criteria were identical to those of the main VALIANT study. The demographics of the echocardiographic participants were similar to the overall study group (13).
Echocardiograms from videotape were digitized and analyses were performed on an offline analysis workstation in a core laboratory. Of the initial cohort, 7 patients were excluded before analysis because of insufficient echocardiographic images and 603 patients were available at baseline for quantitative echocardiographic analysis.
The LV endocardial borders were manually traced at end diastole and end systole at the mitral and papillary short axis level and apical 4- and 2-chamber views from 3 separate cardiac cycles by a single experienced observer. The LV volumes were derived according to the modified biplane Simpson's rule in the apical 4- and 2-chamber views and indexed to body surface area. The EF was calculated in the standard fashion from LV end-diastolic and -systolic volume. Right ventricular (RV) function expressed as the RV fractional area change was assessed quantitatively as the percentage of change in cavity area from end diastole to end systole. Left atrial (LA) volume was assessed by the biplane area-length method from apical 4- and 2-chamber views at end systole from the frame preceding mitral valve opening. The LA volume index was calculated as LA volume/body surface area (ml/m2). Mitral flow velocity was assessed by pulsed wave Doppler study from the apical 4-chambers view by positioning the sample volume at the tip of the mitral leaflets.
The LV mass was indexed to body surface area and LV hypertrophy was considered present when echocardiographically derived LV mass index (LVMi) was >115 g/m2 for men and >95 g/m2 for women (15). The RWT was calculated as 2 × (posterior wall thickness in diastole) / (LV internal diastolic diameter). Increased RWT was present when this ratio was >0.42 (15). The sample was divided into 4 mutually exclusive groups on the basis of LV geometry: concentric hypertrophy (LV hypertrophy and increased RWT), eccentric hypertrophy (LV hypertrophy and normal RWT), concentric remodeling (normal LVMi and increased RWT), and normal geometry (normal LVMi and normal RWT) (15).
Echocardiographic measurements were made in triplicate by a single experienced observer blinded to outcome data using quantitative analysis software. Reproducibility was assessed after studies were randomly chosen and reanalyzed with the observer blinded to the initial results. The coefficient of variability based on the intraobserver reproducibility assessment was 8.3%, 2.7%, 3.0%, and 5.3% for LV volumes, LV mass, LA volume, and RV fractional area change assessment, respectively, and the coefficient of variability based on the interobserver reproducibility assessment for LV mass was 3.0%.
Continuous data were expressed as mean ± standard deviation. Among the 4 categories of LV geometrical patterns, categorical variables were analyzed with the chi-square test. Continuous variables were analyzed with analysis of variance (Scheffe post-hoc) test.
Defined time-dependent clinical outcomes included the primary end point of all-cause mortality and the composite cardiovascular end point and its individual components of cardiovascular death, recurrent MI, heart failure, stroke, and resuscitated sudden death (12). Clinical outcomes were adjudicated by an independent Clinical Endpoints Committee (12). To determine the independent prognostic value of baseline LVMi, LV mass to end-diastolic volume ratio, and RWT and LV geometric patterns, we used a multivariable Cox proportional hazards model. The adjustment model included predictors of mortality identified from the overall VALIANT study: age (in years), primary percutaneous transluminal coronary angioplasty, atrial fibrillation complicating MI, history of diabetes, history of hypertension, prior MI, Killip class, history of congestive heart failure, new left bundle branch block, history of angina, LVEF, estimated glomerular filtration rate, and a history of chronic obstructive pulmonary disease. Both stepwise elimination and backward selection were used to select the most parsimonious set of predictive variables. In addition, we also included in our adjusted model baseline measures of LV end-diastolic volume, LA volume index, and infarct length. To assess the independent prognostic value of RWT above that of LV mass, multivariable analysis was performed after adjustment for LV mass as a continuous variable and the candidate variables listed above in a Cox proportional hazards model. Kaplan-Meier estimates for all-cause mortality and the cardiovascular composite end point were determined according to LV geometric patterns and were presented as event curves. All p values were 2-sided; p < 0.05 was used to determine statistical significance. Statistical analyses were performed using STATA software, version 8.2 (Stata Corp., College Station, Texas).
The baseline LVMi and RWT for the 603 patients in the VALIANT echocardiographic cohort were normally distributed. The mean LVMi (g/m2) was 98.8 ± 28.4 (range: 40.1 to 203.7) and the mean RWT was 0.38 ± 0.08 (range: 0.19 to 0.70). In the VALIANT echocardiographic cohort concentric hypertrophy was present in 76 (12.6%) patients, eccentric hypertrophy in 112 (18.6%) patients, and concentric remodeling was present in 110 (18.2%) patients at baseline. Increased LVMi was associated with higher rates of prior MI, history of hypertension, diabetes mellitus, prior congestive heart failure, and stroke when compared with patients with normal geometry. Moreover, patients with LV hypertrophy were older, more likely to be female, had lower baseline estimated glomerular filtration rate, and lower rates of primary percutaneous transluminal coronary angioplasty (Table 1). No differences were observed among groups with regard to treatment with aspirin, calcium channel blocker, statins, and beta-blockers.
The LV volumes were significantly increased and LVEF and RV function were significantly reduced in patients with eccentric hypertrophy (Table 2). The LA volume index increased significantly with increasing LV mass and was significantly higher in patients with eccentric and concentric hypertrophy. The LV mass to end-diastolic volume ratio and average LV wall thickness increased from normal geometry to concentric hypertrophy. Infarct segment length was lower in patients with LV concentric remodeling and higher in patients with eccentric hypertrophy. Patients with concentric remodeling had significantly lower LV end-systolic volume and transmitral E/A ratio (E = peak early diastolic velocity; A = peak late diastolic velocity). There were no differences at baseline across the 4 groups with regard to deceleration time.
Of the 603 patients in the VALIANT echocardiographic cohort, 103 (17%) patients died, 162 (27%) experienced a composite of death or development of heart failure, and 187 (31%) experienced composite cardiovascular outcomes generated by adding important nonfatal cardiovascular events (recurrent MI, hospitalization for heart failure, resuscitation from cardiac arrest, and stroke) to death from cardiovascular causes after randomization. There were no significant differences in the number of events by treatment group in this cohort (13). When analyzed as a continuous variable, baseline LVMi was a potent univariate predictor of all-cause mortality (hazard ratio [HR]: 1.28; 95% confidence interval [CI]: 1.2 to 1.3), cardiovascular death (HR: 1.30; 95% CI: 1.2 to 1.36), death or heart failure hospitalization (HR: 1.30; 95% CI: 1.30 to 1.40), and cardiovascular composite (HR: 1.28; 95% CI: 1.23 to 1.30), all p < 0.001. In a multivariable adjusted model, each 10 g/m2 increase in LVMi and each 0.1 unit increase in LV mass to end-diastolic volume ratio were independently associated with increased risk for all-cause mortality, cardiovascular death, and death or heart failure hospitalization (each p < 0.001) (Figs. 1A and 1B).
Multivariable Cox proportional hazards models were used to determine the independent prognostic value of left ventricular mass index (LVMi), LV mass/end-diastolic volume (EDV), and relative wall thickness (RWT). The models were adjusted for age (years), primary percutaneous transluminal coronary angioplasty, atrial fibrillation complicating myocardial infarction (MI), history of diabetes, history of hypertension, prior MI, Killip class, history of congestive heart failure (HF), new left bundle branch block, history of angina, LV ejection fraction, estimated glomerular filtration rate, and a history of chronic obstructive pulmonary disease. Each 10 g/m2 increase in LVMi (A), 0.1-U (10%) increase in LV mass to end-diastolic volume ratio (B), and 0.1-U (10%) increase in RWT (C) were independently associated with increased risk for death, cardiovascular (CV) death, and death or heart failure hospitalization (each p < 0.001). Echocardiographically determined LV mass and RWT are significant independent predictors of increased cardiovascular morbidity and mortality in high-risk post-MI patients warranting their routine assessment.
After adjusting for LV mass in addition to other covariates in the model, each 0.1 unit (10%) increase in RWT was independently associated with increased risk for the previously defined end points (each p < 0.001) (Fig. 1C). Both concentric and eccentric hypertrophy were significantly associated with increased risk of adverse outcome, with the highest mortality rates observed for patients with concentric hypertrophy (Figs. 2A,2B, and 3). There was a wide spectrum of risk across the categories of LV geometrical patterns, with early divergence of the Kaplan-Meier curves for the composite end point (Fig. 2B). In a multivariable adjusted model, patients with concentric remodeling or with eccentric or concentric LV hypertrophy had worse outcomes than the patients with normal LV geometry. In particular, patients in the concentric LV hypertrophy group had the highest rate of fatal and nonfatal events (Table 3).
Kaplan-Meier estimates for clinical outcomes for all-cause mortality (A) and the CV composite end point (CV death, recurrent MI, heart failure, stroke, and resuscitated sudden death) (B) were determined for LV geometric patterns and were presented as event curves. There was a wide spectrum of risk across the categories of LV geometrical patterns, with early divergence of the Kaplan-Meier curves for mortality and composite end point, particularly between patients with normal geometry and those with concentric hypertrophy. Concentric hypertrophy carried the greatest CV risk, followed by eccentric hypertrophy, and then concentric remodeling, underscoring the importance of increased LV mass and RWT as important risk predictors following high risk MI. Abbreviations as in Figure 1.
Crude incidence rates per 100 person-years were calculated for the defined time-dependent clinical CV outcomes and depicted as bar graph, for LV geometrical patterns. Concentric hypertrophy carried the greatest incidence rate for adverse CV outcomes including CV mortality, recurrent MI, heart failure, stroke and sudden cardiac death. Even concentric remodeling was associated with poor prognosis compared with patients with normal LV geometry. Concentric hypertrophy had higher incidence rates for CV mortality and heart failure development and also recurrent MI, stroke, and sudden cardiac death. Routine echocardiographic assessment of LV mass and its geometry following a high-risk MI is important. SD = sudden death; other abbreviations as in Figure 1.
In this high-risk cohort of patients with LV systolic dysfunction, heart failure, or both following MI, echocardiographically determined LV mass, RWT, and LV geometry are significant independent predictors of increased cardiovascular morbidity and mortality. Concentric hypertrophy carried the greatest cardiovascular risk, followed by eccentric hypertrophy, and then concentric remodeling. Our results confirm the importance of LV mass and geometry following MI and argue for their routine assessment in high-risk patients with LV systolic dysfunction, heart failure, or both following MI.
Increased LV mass results from increased hemodynamic load and is an independent predictor of subsequent cardiovascular morbidity and all-cause mortality (1,2). Volume and pressure overloads, or a combination of both, cause different LV geometric adaptations including concentric ventricular remodeling, eccentric hypertrophy, and concentric hypertrophy. Geometric patterns identify distinctive pathophysiologic patterns and may be added to LV mass for risk stratification (5–11). Even though cardiovascular risk associated with LV mass is well established in patients with hypertension, the prognostic implication of LV geometry and RWT has not been clearly demonstrated in a high-risk post-MI population (16,17). Our analysis of the VALIANT echocardiographic cohort provides comprehensive information concerning significant cardiovascular risk associated with LV mass and RWT in a population of high-risk post-MI individuals. An important finding of this study shows that concentric LV hypertrophy carries the highest risk of adverse events, even after adjusting for well-established risk factors such as LVEF, hypertension, and estimated glomerular filtration rate, and adds incremental prognostic value over the other known predictors of outcome. Several factors including hypertension and activation of the renin-angiotensin-aldosterone system induce LV hypertrophy and progression of atherosclerosis. Pathologic increase in LV mass beyond the need to compensate for increased cardiac load is found when LV geometry is concentric (18,19) and is associated with increased collagen deposition in the extracellular matrix and around the intramyocardial coronary arteries with medial thickening of the intramyocardial coronary arteries and disturbances of myocardial blood flow (20,21). Although myocardial afterload is the prime stimulus that promotes the cascade of biological events leading to ventricular hypertrophy to reduce wall stress, concentric LV hypertrophy is eventually associated with increased cardiovascular risk (22). Left ventricular hypertrophy secondary to hypertension, infarction, obesity, or valvular heart disease leads to shifts toward glycolytic metabolism, disorganization of the sarcomere, alterations in calcium handling, changes in contractility, loss of myocytes with fibrotic replacement, systolic and diastolic dysfunction, and electrical remodeling resulting in alterations in myocardial metabolism, structure, and function with increasing severity of LV hypertrophy (23). These structural, metabolic, and functional alterations possibly associate LV hypertrophy with adverse cardiovascular risk and heart failure development.
In addition, the present study demonstrates that increasing baseline LV mass is also associated with increasing incidence of resuscitated sudden death. Left ventricular hypertrophy has long been known to be associated with sudden cardiac death and increased risk of ventricular arrhythmias (24–26), and it may be related to prolongation of action potential, increased dispersion of refractoriness, and lowering of the ventricular fibrillation threshold (24). Of note, we also observed increasing incidence of stroke associated with abnormal LV geometry, both concentric hypertrophy and concentric remodeling were associated with an increased risk of stroke. Left ventricular hypertrophy has long been associated with risk of ischemic stroke (27–29). Recently, Di Tullio et al. (30) reported association of abnormal LV geometry and RWT with stroke risk in a population-based case control study. Our study extends those findings to a high-risk post-MI population.
It is also noteworthy that despite being associated with similar left and right systolic function, concentric LV remodeling was also associated with poor prognosis compared with patients with normal LV geometry in this high-risk post-MI population. In our observations, concentric remodeling was associated with a 3-fold increase in fatal and nonfatal cardiovascular events following a high-risk MI. The association of concentric remodeling with increased risk is supported by Verdecchia et al. (11), who demonstrated that in the presence of normal LV mass, concentric LV remodeling reflecting a nearly pure pressure overload was associated with worse outcome. These observations suggest that both chamber dilation in the form of eccentric hypertrophy and increased RWT in the form of concentric LV hypertrophy and concentric remodeling are independently related to adverse cardiovascular events.
Although our findings are strengthened by involving a larger cohort of randomized subjects receiving contemporary post-MI therapy and the nearly complete follow-up associated with this trial, some limitations should be noted. First, 2-dimensional echocardiography is limited in its accuracy for measuring LV mass because all methods assume a uniform LV thickness, which is not the case in areas of chronic MI or with geometric deformity of the LV cavity. However, the M-mode methods based on the simple cube-function formula have repeatedly been shown to give reasonably accurate LV mass measurements in necropsy validation studies. In addition, the simplicity and ease of this technique has made it possible for application to large-scale clinical and epidemiological studies and to relate LV mass and its change over time to clinical outcomes (31). On the other hand, the 2-dimensional methods for measuring LV mass that are based on the area-length formula and the truncated ellipsoid model might be more accurate, but because this is also expertise-dependent and time-consuming, its applicability is limited to a large-scale study. None of the methods described to measure LV mass are validated in the post-MI setting. However, despite its limitations, we do not expect the degree of wall thickness to change abruptly after an acute MI and the method used in this study was applied in a blinded fashion to a large sample of patients; therefore, the association between increased LV mass, abnormal LV geometry, and cardiovascular risk is likely to be real. In addition, first, baseline echocardiograms in the VALIANT echocardiographic study were obtained during the early post-MI period, thus precluding any significant LV enlargement and were devoid of any LV aneurysm. Second, we did not assess for serial changes in blood pressure and in LV mass and its geometrical patterns and potential influence on cardiovascular risk. Finally, our results are predominantly applicable to the high-risk cohort of VALIANT, which limits generalization to the broader group of post-MI patients.
Echocardiographically determined LV mass and its geometrical patterns are important independent predictors of increased morbidity and mortality following high-risk MI. Concentric LV hypertrophy carries the greatest risk of adverse cardiovascular events including death. Even the presence of concentric geometry in the absence of increased LV mass is associated with an increased risk of subsequent cardiovascular complications, underscoring the importance of increased baseline LV mass and RWT as important risk predictors in patients following high-risk MI. Our findings demonstrate that routine assessment of LV mass and RWT can be used to better risk-stratify patients following high-risk MI with LV systolic dysfunction, heart failure, or both, and raise the question of whether specific therapies can be developed to improve prognosis in these high-risk patients.
For an accompanying slide set on the VALIANT study, please see the online version of this article.
Drs. Ghali, Arnold, McMurray, Pfeffer, Califf, and Solomon have received research funding from Novartis Pharmaceuticals. Dr. Velazquez has served as a consultant for or has received honorariums from Novartis Pharmaceuticals.
Revision received May 1, 2008.
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