Age, Increased Left Ventricular Mass, and Lower Regional Myocardial Perfusion Are Related to Greater Extent of Myocardial Dyssynchrony in Asymptomatic Individuals
The Multi-Ethnic Study of Atherosclerosis
Background— Age and left ventricular (LV) hypertrophy are risk factors for the development of LV dysfunction and congestive heart failure. Our goal was to study the relationships of LV mass and age with myocardial dyssynchrony among asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis.
Methods and Results— A total of 1100 individuals underwent tagged magnetic resonance imaging. Regional LV function was analyzed with the use of harmonic phase imaging. Time to peak systolic circumferential strain and strain rate were measured in 12 segments, and myocardial dyssynchrony was expressed as the SD of time to peak strain and strain rate. Relationships of age, LV mass, and myocardial perfusion with timing of strain, strain rate, and dyssynchrony were studied. There was a positive relationship between age and time to peak strain before (regression coefficient=0.37 ms/year of age; 95% confidence interval, 0.05 to 0.70; P=0.025) and after adjustment for demographic characteristics and risk factors (P=0.007). Positive associations between age and SD of time to peak strain (regression coefficient=0.33 ms/year of age; P=0.002) and SD of time to peak systolic strain rate were documented (P=0.045). Importantly, we found that LV mass index is directly related to time to peak strain (P<0.001), time to peak strain rate, and the SD of time to strain rate (P=0.001 for all). Finally, decreased myocardial perfusion at rest was associated with delayed contraction and increased extent of dyssynchrony.
Conclusions— In asymptomatic individuals, age, increased LV mass, and decreased myocardial perfusion are related to delayed myocardial contraction and greater extent of dyssynchrony. Increased dyssynchrony may mediate the association of myocardial dysfunction with age and LV hypertrophy.
Received April 23, 2008; accepted June 26, 2009.
Heart failure constitutes a major health problem worldwide. Approximately 5 million patients in the United States suffer from congestive heart failure (CHF), and 500 000 new patients are diagnosed annually as having this condition.1 The prevalence of heart failure increases with age, and approximately 6% to 10% of individuals older than 65 years are diagnosed as having heart failure.2 With the aging of the general population, the incidence and prevalence of CHF are expected to increase.
Clinical Perspective on p 866
Left ventricular (LV) remodeling and hypertrophy are also associated with the development of CHF and an increased incidence of other major cardiovascular events, including sudden death.3,4 In a previous study based on the Multi-Ethnic Study of Atherosclerosis (MESA) database, LV remodeling was associated with decreased systolic regional LV function.5
Coordinated contraction of the LV myocardium is necessary for efficient LV chamber performance. Indeed, conduction abnormalities in the form of left bundle-branch block have been associated with global LV dysfunction.6 Tagged magnetic resonance imaging (MRI) studies demonstrated that creation of dyssynchronized electric activation with the use of right ventricular pacing causes redistribution of regional myocardial work with markedly reduced myocardial deformation in regions adjacent to the pacing site and greater workload in remote areas. This redistribution has been associated with changes in myocardial perfusion, as well as with LV structural changes.7
Several techniques have been used to evaluate mechanical dyssynchrony. The most commonly used modality has been echocardiography with the use of tissue Doppler imaging or speckle tracking. However, tagged MRI is a more powerful tool for assessing myocardial dyssynchrony by virtue of its ability to evaluate myocardial deformation noninvasively, unlimited by scanning angles or acoustic windows.
Our aim was to explore the relationship between age, increased LV mass, and the extent of dyssynchrony in an asymptomatic population free of cardiovascular disease. This would allow insight into the mechanisms associated with the development of LV dysfunction and heart failure in these populations.
MESA is a prospective cohort study designed to evaluate mechanisms underlying the development and progression of subclinical cardiovascular disease in asymptomatic individuals.8 A total of 6814 men and women 45 to 85 years of age from different ethnicities (white, black, Hispanic, and Chinese American) were included in the study. Individuals with cardiac symptoms or known cardiovascular disease were excluded. Cardiac MRI was performed as part of the baseline examination. Of the entire study population, 1100 consecutive participants agreed to undergo tagged MRI studies in 6 centers (Wake Forest University, Winston-Salem, NC; Columbia University, New York, NY; Johns Hopkins University, Baltimore, Md; University of Minnesota, Minneapolis; Northwestern University, Chicago, Ill; and University of California at Los Angeles). The study protocol was approved by the institutional review boards of each participating center, and informed consent was obtained from each participant.
Two hundred fifty-five individuals among the 1066 MESA participants enrolled at St Paul, Minn, underwent tagged MRI. All participants enrolled in that center were invited to participate in a substudy of contrast-enhanced perfusion imaging. Individuals with known sensitivity to gadolinium or adenosine, bradyarrhythmias, asthma, or chronic obstructive pulmonary disease were excluded. Two hundred thirty-four participants underwent myocardial perfusion studies, and 74 individuals underwent both myocardial MRI tagging and contrast-enhanced perfusion studies. Results from this group of individuals are included in the analysis of the association between perfusion and dyssynchrony.
Tagged MRI Studies
Tagged MR images were acquired by whole-body 1.5-T scanners with ECG-triggered segmented k-space fast spoiled gradient-echo pulse sequence during breath holds. After the standard protocol was completed, 3 tagged short-axis slices (base to apex) were obtained with the use of spatial modulation of magnetization encoding gradients. Settings are described in the online-only Data Supplement. LV mass was determined for each participant with the use of dedicated commercially available software (MASS, version 4.2, Medis, Leiden, the Netherlands) at end-diastole, as described previously by Natori et al.9
Short-axis tagged slices were analyzed with the use of harmonic phase imaging. This method (Diagnosoft, Palo Alto, Calif) enables fast determination of myocardial strain,10 including circumferential strain and strain rate from 3 short-axis slices (basal, midventricular, and apex) and 4 regions (septum, anterior, posterior, and lateral walls). Times from end-diastole to peak systolic strain and strain rate were also measured (Figure 1).
SD of time to peak systolic strain and time to peak systolic strain rate in 12 regions (3 slices×4 regions) was used to evaluate the extent of myocardial dyssynchrony. This approach is analogous to the method described previously by Yu et al11 using echocardiography.
To assess the validity of the SD of time to peak systolic strain and strain rate, we studied their correlation with an established index of dyssynchrony (ie, lateral to septal wall time delay). The correlation between lateral-septal delay and the SD of the time to peak systolic strain rate was good (r=0.60, P<0.001). In contrast, the correlation between the absolute difference and SD of time to peak systolic strain was weaker (r=0.26, P<0.001).
MRI Perfusion Study
T1-weighted gradient-echo imaging with magnetization saturation was used to cover 2 to 3 short-axis slices during the first pass of the contrast bolus through the LV (cavity and myocardium). Gd-DPTA at a dose of 0.04 mmol/kg body weight (Magnevist, Berlex, Wayne, NJ) was administered intravenously at a rate of 7 mL/s. First-pass scan was performed at rest, followed by a second scan 15 minutes later during hyperemia induced by adenosine (0.14 mg/kg per minute for 3 minutes, before the onset of scanning). Myocardial blood flow (mL/min per gram tissue) at rest and during hyperemia was determined as described previously.12
The associations of mean time to peak systolic strain, mean time to peak systolic strain rate (averaged across the 12 regions), extent of dyssynchrony (expressed as the SD to time to peak strain or strain rate in 12 regions) with age, sex, and LV mass were studied. LV mass index (LV mass/height2.7) and age were studied as continuous and as categorical variables with the use of quartiles for LV mass index and age groups (45 to 54, 55 to 64, 65 to 74, and 75 to 85 years). Multiple linear regression models were used to examine relations of time to peak systolic strain, strain rate, and their corresponding SDs as dependent variables, whereas demographic parameters and risk factors served as independent variables.
Three sets of multivariable models were examined in a hierarchical fashion: model 1: unadjusted; model 2: adjusted for sex, age (when LV mass index was studied), ethnicity, and body mass index (when age was used); and model 3: model 2 with additional adjustments for history of diabetes mellitus, smoking (never, former, and current smokers), systolic and diastolic blood pressures, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and antihypertensive therapy. Relationships between mean blood flow at rest and during adenosine-induced hyperemia and average time to peak strain, strain rate, and dyssynchrony were also determined by multivariable linear regression analysis.
The normality of residuals from the linear regression models was assessed via standardized normal probability (P-P) plots as well as by plotting the quantiles of a variable against the quantiles of a normal distribution showing no deviation from normality in the middle range of data as well as near the tails. Skewed plots of residual versus fitted values from age–specific regression models did not indicate a discernible pattern or heteroscedasticity in residuals, suggesting that no important deviations from linear model assumptions had occurred. Because the relationship between SD of time to peak strain rate and LV mass/height2.7 was not linear, we studied the relationships between mass index and strain times and dyssynchrony using LV mass index quartiles. Differences were considered significant if P<0.05. All reported P values are 2-sided.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
The mean age of the study population was 66 years. Fifty-four percent (562/1100) were men. Study participants were mildly overweight (body mass index, 27.8±4.6 kg/m2) (mean±SD). A considerable percentage of individuals had risk factors including hypertension (43.6%) and diabetes mellitus (17.5%) (Table 1). Approximately 50% were either former or current smokers, and 19.3% of the study participants were treated for hyperlipidemia. Mean global LV ejection fraction was 68.6±7.6%, and LV mass was 146.6±40.1 g.
Mean±SD time to peak systolic strain was 315.4±53.6 ms, and the time to peak systolic strain rate was 106.6±29.8 ms. Extent of myocardial dyssynchrony, defined as the SD of the time to peak systolic strain and strain rate in 12 regions, was 84.9±30.6 and 47.4±22.5 ms, respectively. The means and distributions of these parameters are presented in the online-only Data Supplement (Table I).
Relationships of Sex, Time to Peak Systolic Strain, and Strain Rate With Dyssynchrony
There were no significant sex-related differences in time to peak systolic strain (317.6±51.5 and 312.7±55.9 ms in men and women, respectively; P=0.14). Time to peak systolic strain rate tended to be greater in men (P=0.07), whereas SD of time to peak systolic strain tended to be higher in women (86.5±30.8 versus 83.4±30.4 ms; P=0.09).
Relationships of Age, Time to Peak Systolic Strain, and Strain Rate With Dyssynchrony
There was a positive relationship between age and time to peak systolic strain (regression coefficient [RC]=0.37 ms/1 year of age, P=0.025 before adjustment; and RC=0.49 ms/1 year of age, P=0.007 after adjustment for demographic parameters and risk factors). In contrast, there was an inverse relationship between age and time to peak systolic strain rate (P=0.042). However, after multivariable adjustment, the latter association became nonsignificant. Interestingly, there were direct associations between age and SD of time to peak systolic strain and SD of time to peak systolic strain rate (Table 2, Figure 2). Analysis with the use of age group categories rather than age as continuous variable yielded similar results (Table I in the online-only Data Supplement).
Relationships of LV Mass Index, Time to Peak Systolic Strain, and Strain Rate With Myocardial Dyssynchrony
A positive linear relationship was noted between the time to peak systolic strain and LV mass index [RC=1.11 ms/(1 g · m2.7); 95% confidence interval, 0.71 to 1.52; P<0.001] before adjustment. After adjustment for demographic parameters and risk factors, this association remained significant [RC=1.20 ms/(1 g · m2.7); P<0.001]. A similar direct association was also found between time to peak systolic strain rate and LV mass index (P<0.001 after adjustment). Moreover, there was a significant positive relationship between LV mass index and SD of time to peak systolic stain rate (0.016) (Table 3, Figure 3). After multivariable adjustment, this association remained significant (adjusted difference between the first and fourth quartiles was 5.4 ms; P=0.022). In contrast, the association between LV mass index and SD of the time to peak systolic strain was not significant. Analysis with the use of LV mass indexed by body surface area yielded similar results (data not shown). Importantly, there were no significant relationships between the extent of concentric remodeling expressed as the mass/volume ratio and the times of peak systolic strain, strain rate, or their corresponding SDs (data not shown).
Relationships of Myocardial Perfusion at Rest and During Adenosine-Induced Hyperemia With Time to Peak Systolic Strain, Strain Rate, and Dyssynchrony
To further explore the mechanisms underlying the associations between LV mass and age with myocardial dyssynchrony, the association between myocardial perfusion and the times to peak systolic strain, strain rate, and their SD were studied in an ancillary study including 74 participants who underwent both contrast-enhanced perfusion and tagged MRI studies.
A significant increase in time to peak systolic strain in the lowest tertile of myocardial blood flow at rest was found (time to peak systolic strain in the lowest tertile was 329.9 ms versus 294.5 ms in the highest; P=0.034). In addition, time to peak systolic strain rate was longer in the lowest compared with the highest myocardial blood flow tertile (P=0.03), and the SD of time to peak systolic strain rate was significantly greater in the group with the lowest myocardial blood flow at rest (60.0 ms in the lowest myocardial blood flow tertile versus 39.8 ms in the highest tertile; P=0.013) (Table III in the online-only Data Supplement).
The associations between myocardial blood flow at rest with time to peak systolic strain, time to peak systolic strain rate, and SD of time to peak systolic strain rate became stronger after multivariable adjustment (Table 4, model 3). The relationship between SD of the time to peak systolic strain and myocardial blood flow at rest tended to be significant (RC=−28.1 ms per 1 mL/min per gram blood flow; 95% confidence interval, −56.8 to 0.67; P=0.055). In contrast, the associations between the time to peak systolic strain, strain rate, and their SD with myocardial blood flow during adenosine-induced hyperemia were nonsignificant.
Relationship of Global LV Function and Volumes and QRS Width With Time to Peak Systolic Strain, Strain Rate, and Dyssynchrony
After multivariable adjustment for demographic characteristics, risk factors, and treatment, lower ejection fraction was associated with greater time to peak systolic strain (RC=−0.018 ms/1% ejection fraction; 95% confidence interval, −0.026 to −0.009; P<0.001) and strain rate (RC=−0.047 ms/1% ejection fraction; P<0.001). In contrast, there was no significant association between ejection fraction and the SD of time to peak systolic strain (P=0.11) or strain rate (P=0.086). Increased LV volumes (systolic and diastolic) were related to greater contraction times and myocardial dyssynchrony (Tables IV and V in the online-only Data Supplement). Interestingly, there were significant relationships between QRS width and both time to peak systolic strain rate and its SD (P<0.001 and P=0.003, respectively; Table VI in the online-only Data Supplement).
Finally, there were no relationships between age and absolute peak systolic strain and strain rates, whereas peak diastolic strain rates were lower with increased age in men. On the other hand, increased LV mass was related to decreased peak systolic strain in men and to peak systolic and diastolic strain rate in both sexes (Tables VII and VIII in the online-only Data Supplement, respectively).
In the present study, we examined relationships of the timing of myocardial contraction and the extent of dyssynchrony with age and LV mass in asymptomatic individuals without history of cardiovascular disease. LV hypertrophy and age are strongly related to the development of heart failure. Significant associations between age and time to peak systolic strain, as well as age and myocardial dyssynchrony, were detected. In addition, higher LV mass was related to both delayed systolic contraction and greater LV dyssynchrony, expressed as the SD of time to peak strain rate. These results demonstrate that aging and LV hypertrophy influence the coordination of myocardial contraction before the onset of overt LV dysfunction and symptomatic disease.
To gain further insight into the mechanisms underlying these relationships, associations between myocardial perfusion and time to peak systolic strain and strain rate were studied in a subset of participants who underwent tagged MRI and contrast-enhanced myocardial perfusion studies. Lower myocardial perfusion at rest was associated with both an increased time to peak systolic deformation and a greater extent of myocardial dyssynchrony.
Age has been demonstrated as an important risk factor for the development of CHF.1,2 Results from the Cardiovascular Health Study, for example, indicate that approximately half of the elderly patients who develop CHF have normal global LV function. These individuals were considered to have diastolic dysfunction.13,14 Mortality of patients with heart failure and preserved systolic function may be lower compared with patients with abnormal systolic function,15 although the results from a recent study suggest otherwise.16 In elderly patients, diastolic filling rates are reduced,17 and it has been shown that both relaxation and ventricular stiffness are abnormal in these patients.18 However, patients with heart failure and preserved ejection fraction may exhibit abnormal systolic function when evaluated by more sophisticated measures of myocardial performance such as impaired long-axis shortening and longitudinal mitral annulus velocities.19,20 In addition, previous studies21 have suggested that patients with diastolic HF demonstrate increased diastolic as well as systolic dyssynchrony. In this regard, in the present study, we found changes in systolic contractile performance (eg, systolic dyssynchrony) in conditions that are commonly associated with diastolic dysfunction, eg, increased age and LV hypertrophy, despite preserved global systolic LV function. The combination of these findings suggests that diastolic and systolic dysfunction are not distinct entities and in fact represent different aspects of a spectrum of altered myocardial mechanical behavior that include diastolic and systolic abnormalities of varying contributions.
Bonow et al22 demonstrated by radionuclide angiography that aging was associated with delayed and decreased early diastolic filling and that these changes were related to regional LV dyssynchrony assessed from regional volume curves. Fonseca et al23 showed that in elderly individuals there is an increase in regional asynchrony in time to peak relaxation. In the present study, we confirm those findings, suggesting that increased age is indeed associated with a greater extent of dyssynchrony. This may impinge on early diastolic relaxation through increased postsystolic shortening24 and discoordinate myocardial strain. Delayed myocardial contraction and dyssynchrony may result from myocardial fibrosis, especially in hypertensive patients25 with silent ischemia or infarction, potentially contributing to further electromechanical uncoupling. In addition, conduction abnormalities could affect the timing of regional myocardial shortening and cause contractile dyssynchrony. Further studies are needed to clarify the mechanisms underlying these associations.
LV hypertrophy, especially in the form of concentric hypertrophy, is associated with the development of CHF and increased incidence of other major cardiovascular events, including sudden death.3,4 Initially, LV concentric remodeling is associated with decreased regional LV function, manifested as reduced midwall circumferential shortening despite preserved ejection fraction.26,27 Eventually, however, patients with LV hypertrophy tend to develop global systolic dysfunction.28 In our study, we show that increased LV mass is related to delayed regional LV contraction and myocardial dyssynchrony, expressed as SD of time to peak systolic strain rate among individuals without history of cardiovascular disease. In contrast, there was no significant relationship between LV mass and SD of time to peak systolic strain. A potential explanation is that increased LV mass might preferentially affect the early phase of systolic contraction, manifested as the time to peak systolic strain rate. Another possibility is that strain rate is a more sensitive indicator of systolic contractility than strain. Thus, the earliest changes in myocardial contractility and dyssynchrony would manifest as changes in strain rate rather than strain.
Importantly, there was no significant relationship between the magnitude of concentric hypertrophy (expressed as LV mass/volume ratio) and the timing of regional deformation or LV dyssynchrony. These findings might indicate that LV enlargement and absolute increased LV size (LV mass and volumes) rather than concentric hypertrophy are related to LV dyssynchrony. This finding contrasts with the negative relation between concentric remodeling and peak systolic strain found in previous work.5
It is important to emphasize that the present study is cross-sectional. Therefore, temporality cannot be determined. For example, it is possible that myocardial dyssynchrony might have caused subtle LV dysfunction with compensatory increased LV mass. In addition, survival bias might have affected the results because only asymptomatic individuals without documented cardiovascular disease were included. Whether MESA cohort participants with increased extent of dyssynchrony associated with greater LV mass will develop symptoms of CHF is to be explored.
Finally, we studied the relationship between myocardial perfusion and the timing and SD of LV contraction. In a previous study, we observed that myocardial perfusion reserve, expressed as perfusion during adenosine-induced hyperemia, was associated with decreased regional LV function, manifested as lower peak systolic circumferential shortening.12 In the present work, with the same database, decreased regional perfusion at rest was shown to be associated with delayed contraction and greater extent of dyssynchrony, although there was no relationship between perfusion during hyperemia and dyssynchrony. Again, these relationships may be due to increased postsystolic shortening or delayed electromechanical coupling in regions with reduced perfusion.
The present work includes 1100 asymptomatic individuals from the MESA cohort, making it one of the largest tagged MRI studies of which we are aware. The study cohort was multiethnic, thus enhancing the generalization of the study results. Tagged MRI is a robust technique for analyzing regional LV function without limitations of acoustic window or scanning angles, although its temporal resolution (≈40 ms) is inferior to echocardiography.
This study is cross-sectional. Therefore, cause-effect relationships cannot be established.
Moreover, the results of the present study should be interpreted in view of the study design and the exclusion of individuals with symptoms or history of cardiovascular disease. Hence, patients with the most pronounced degree of LV hypertrophy and/or LV dysfunction might have been excluded, thus potentially blunting the strength of the reported associations.
There are several methods for assessing myocardial dyssynchrony. As an index of intraventricular dyssynchrony, we used the SD of the time to peak systolic strain and strain rate in 12 regions, a modification of a method used by Yu et al.11 This index was found to have better specificity and sensitivity than alternative methods for predicting reverse remodeling after resynchronization therapy.
Only circumferential strain was used because the results of circumferential strain were found to be more reproducible than radial strain.29 In work done by Carlsson et al,30 it has been shown that a major contribution to the overall stroke volume (60%) is generated by longitudinal atrioventricular plane displacement. Our current database does not allow us to examine the potential contribution of longitudinal atrioventricular displacement to myocardial dyssynchrony. Finally, we used LV mass indexed by height2.7. Repeated analyses of absolute as well as LV mass indexed by body surface area yielded similar results.
In conclusion, among asymptomatic individuals without history or symptoms of cardiovascular disease, aging, increased LV mass, and reduced myocardial perfusion are associated with delayed regional myocardial contraction and a greater extent of myocardial dyssynchrony. These associations may reflect incipient myocardial impairment preceding the development of overt LV dysfunction and symptomatic disease.
The authors thank the participants of the MESA trial and the entire community of MESA investigators and staff for their support and valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.
Sources of Funding
This study was supported by a National Heart, Lung, and Blood Institute grant (RO1-HL66075-01) and MESA contracts (NO1-HC-95162, NO1-HC-95168, and NO1-HC-95169). Drs Lima and Bluemke were also supported by the Johns Hopkins Reynolds Center.
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Age and myocardial hypertrophy are associated with the development of left ventricular (LV) dysfunction and heart failure. Myocardial dyssynchrony is also related to the development and progression of heart failure. Our goal was to study the relationship of LV mass and age with dyssynchrony in asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis and to obtain more insight into the mechanisms underlying the development of myocardial dysfunction. A total of 1100 individuals underwent tagged magnetic resonance imaging. Their regional LV function was analyzed with the use of time parameters of myocardial deformation including time to peak systolic strain and strain rate. Myocardial dyssynchrony was expressed by SD of time to peak strain and strain rate. There was a direct relationship between age and delayed time to peak strain and a greater extent of dyssynchrony. Importantly, there was also significant association between LV mass and time to peak strain, time to peak strain rate, and the SD of time to strain rate. In a subset of patients (n=74), the relationship between myocardial perfusion and timing of contraction was studied. Decreased myocardial perfusion at rest was associated with delayed contraction and increased extent of dyssynchrony. These new data may enhance our understanding of the development of myocardial dysfunction and its possible prevention. We believe that myocardial dyssynchrony may explain, at least partly, the well-known association between aging and LV hypertrophy and LV dysfunction. This association may be mediated by changes in myocardial perfusion. However, the temporal relationships between aging, LV hypertrophy, reduced myocardial perfusion, dyssynchrony, and LV dysfunction should be clarified further.
Clinical trial registration information—URL:http://www.clinicaltrials.gov. Unique identifier: NCT00005487.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.787408/DC1.