This study demonstrates marked age-associated differences in LV structure and function in the largest cohort of multi-ethnic individuals studied to date with cardiac MRI. In this cohort, age was associated with a phenotype of LV remodeling marked by several specific structural features and coincident with impaired systolic as well as diastolic myocardial function. Furthermore, this LV remodeling conferred significant risk for cardiovascular events. Taken together, these findings suggest that processes related to biologic aging likely contribute to alterations in LV structure and function that, in turn, predispose to greater cardiovascular risk.
The major age-associated differences in LV structure and function found in this study were three-fold. First, age was associated with a markedly increased M/V ratio, consistent with the age-associated LV hypertrophic remodeling7,33
and increase in relative wall thickness34
found in prior studies. However, the increased M/V ratio in this study was not due to increased LV mass, as suggested by some prior population studies,7
but instead driven by a substantial decline in LV volumes out of proportion to any alterations in mass. Earlier investigations used echocardiographic methods for estimating LV mass, including M-mode, which are less able than cardiac MRI to distinguish between concentric remodeling and concentric hypertrophy.34–36
On the other hand, prior MRI studies in smaller samples have found similarly preserved or reduced LV mass in older compared to younger adults.17,28
An explanation for age-associated hypertrophy, in the absence of increased mass, is offered by histomorphometric studies in humans and animals showing that as the absolute number of myocytes decreases in older age, remaining myocytes tend to hypertrophy in size.8,19,37,38
These studies also found that the number of collagen fibers and nonenzymatic cross-linking in myocardium increases with age. Therefore, despite progressive myocyte dropout in aging, myocyte hypertrophy and increased collagen concentration appear to relatively preserve but not increase LV mass. This type of age-based ventricular remodeling is likely also related to the well-described coupling of ventricular and vascular stiffening processes that can occur over a life course.34,39
Indeed, our ventricular findings were observed independent from but also in the setting of a concurrent age-associated rise in pulse pressure, a recognized index of arterial stiffness.
Secondly, we found an age-associated decline in SV that was accompanied, paradoxically, by a modestly enhanced EF. Physiologic studies have previously documented an age-associated deterioration in global LV function as represented by indices of SV but not EF.27
Conversely, other reports have described increased fractional shortening34
or at least preserved EF40
in older compared to younger subjects. In our study, the apparent paradox of rising EF in the face of a falling SV appeared driven by the overall decline in LV chamber volumes, particularly in LVESV despite a correspondingly greater reduction in LVEDV across all age groups (, ). Given that EF is the ratio of SV over LVEDV, we were able to observe that as SV decreased, EF actually increased (see hatched bars in ). Prior studies have suggested that age is associated with preserved EF but greater LV volumes.41–43
However, these earlier studies assessed LV volumes using radionuclide ventriculography, which is limited by varying attenuation between anterior and posterior walls, background subtraction errors, and geometric assumptions when compared to cardiac MRI.44
Finally, in the setting of falling SV and rising EF, age was also associated with abnormal systolic and diastolic strain, representing early myocardial dysfunction. Age-related myocyte depletion, combined with increased myocardial collagen deposition, may well contribute to impaired contractility and abnormal diastolic function as well as reduced LV volumes. Additionally, the discrepancy between the age-associated increase in ejection fraction and decline in circumferential shortening may be in part due to the phenomenon of cross fiber shortening,45,46
whereby the ventricle compensates for impaired contractile function through concentric hypertrophy and associated reliance on shortening of cross fibers to maintain systolic wall thickening and ejection fraction. Prior studies have found abnormal relaxation and diastolic strain in older adults34
but overall myocardial systolic function was generally thought to remain intact. On the other hand, reduced systolic strain in the presence of LV hypertrophy and preserved EF has been found in association with hypertension and, in the MESA cohort, systolic circumferential strain was progressively lower in participants with increasing M/V ratios.47
This study suggests that these same features are associated with age even after adjusting for hypertension and BP indices. Age-associated abnormalities in myocardial strain may be yet another sign of abnormal coupling of ventricular and vascular remodeling, particularly as we have previously observed abnormal myocardial strain in the setting of increased arterial stiffness.48
The most representative feature of age-associated remodeling was increased M/V ratio, reflective of a hypertrophic process occurring in the setting of progressively reduced LV volumes. Prior studies have reported on the relation of LV hypertrophy with a variety of important cardiovascular outcomes.33,49
Interestingly, we found that an increased M/V ratio conferred a higher hazard for total cardiovascular events in younger compared to older age. This finding may reflect survivor bias in the MESA population and/or suggest that individuals who develop hypertrophic remodeling earlier in life have greater risk. This higher risk in younger adults may be related to subclinical coronary artery disease and/or hypertensive heart disease. However, the relation of M/V ratio to cardiovascular outcomes was significant even after adjustment for risk factors including hypertension.
The generalizability of our results may be limited by selection and survivor biases. Since MESA participants had no known cardiovascular disease at baseline, older individuals in this cohort represent a particularly healthy sample; therefore, present findings may underestimate true age-related differences. Our sample did not include persons <45 or >84 years of age. Additionally, analyses of age-associated LV remodeling were cross-sectional across a large cohort of individuals of varying age groups and did not account for the possible influence of birth cohort. Therefore, temporal relationships cannot be inferred for analyses of age-associated LV remodeling, although these may be the subject of future longitudinal investigations using serial cardiac MRI. We also were not able to adjust measures of peak systolic and diastolic strain for wall stress, which should ideally be considered in detailed investigations of contractile function and relaxation.50
Our findings suggest that human aging is associated with specific alterations of LV structure and function marked by an increase in M/V ratio, driven by a reduction in LV volumes out of proportion to declining LV mass. Moreover, age is independently associated with a parallel reduction in SV and progressive systolic and diastolic myocardial dysfunction, despite a modestly enhanced EF. Additionally, this study demonstrates a significant relationship between this phenotype of LV remodeling and adverse cardiovascular outcomes. Further investigations are needed to elucidate the etiology of such age-associated processes.