Author + information
- Steffen E. Petersen, MD, DPhil, MPH∗ ()
- Department of Advanced Cardiovascular Imaging, William Harvey Research Institute, National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, London, United Kingdom
- ↵∗Reprint requests and correspondence:
Prof. Steffen E. Petersen, Department of Advanced Cardiovascular Imaging, William Harvey Research Institute, National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts, Charterhouse Square, London EC1M 6BQ, United Kingdom.
Cardiac remodeling frequently leads to heart failure with substantial mortality, morbidity, and economic burden to society. The prevalence of heart failure is approximately 2% to 4% of the population in Europe with a major impact on health care expenditure (1). Both the incidence and prevalence of heart failure will increase due to an aging population, an increasing prevalence of diabetes and hypertension, and the improved prognosis of most cardiovascular diseases. Despite the astronomical burden of the disease due to maladaptive cardiac remodeling, our current understanding of the interplay of nongenetic and genetic factors contributing to the remodeling process is still limited.
The MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective cohort study designed to evaluate the mechanisms that lead to the development and progression of subclinical cardiovascular disease. In this study, 5,004 individuals from 4 ethnic groups asymptomatic for cardiovascular disease had a cardiac magnetic resonance (CMR) scan at baseline (2000 to 2002). Of these participants, 3,016 underwent a follow-up CMR (2010 to 2012). It is the largest population-based study to date with serial CMR data over a decade, which provides tremendous opportunities to study influencing factors on cardiac remodeling. Partly due to the open and collaborative study design with data distribution directly to the study investigators, MESA has recently reached a significant milestone of 1,000 publications from over 2,800 investigators.
Zemrak et al. (2) used MESA’s serial CMR data for the first time in 2014 to study cardiac remodeling over a 10-year period. This study demonstrated that more extensive left ventricular (LV) trabeculation (greater ratio of noncompacted to compacted layer thickness) did not predict the development of clinically significant LV enlargement or systolic dysfunction over a decade of follow-up in this asymptomatic cohort. These findings are clinically important as they should guide clinical decision making in the common scenario where patients with marked LV trabeculation and low pre-test probability of LV noncompaction have no clear need for follow-up imaging or pharmacotherapy. In addition, the Zemrak et al. (2) study already showed that LV volumes reduce over time as people age by 10 years.
In 2015, Eng et al. (3) confirmed the reduction of LV volumes observed by Zemrak et al. (2) and extended the findings to other LV structural and functional measures. Interestingly, in 2009, Cheng et al. (4) presented in age-based cross-sectional analyses of the MESA baseline CMR data, that absolute LV mass incrementally decreased across increasing age groups by 0.3 g per year (p < 0.0001), and this trend was observed in both sexes. Eng et al. (3) demonstrated the importance of longitudinal studies, as longitudinal LV mass increase in men was in contrast to the cross-sectional pattern of LV mass decrease observed by Cheng et al. (4). Longitudinally, LV mass decreases in women, LV end-diastolic volume decreases in men and women, and LV stroke volume and LV mass-to-volume ratio increase in both sexes.
Ambale Venkatesh et al. (5) assessed associations of changes over 10 years in LV structure and function with myocardial replacement fibrosis (late gadolinium enhancement) and diffuse fibrosis (post-contrast T1 mapping). The presence of replacement scar after 10-year follow-up was temporally associated with 3% decrease in LV ejection fraction and 0.7% greater LV end-diastolic volume indexed to body surface area in men only. Diffuse fibrosis after 10-year follow-up was longitudinally associated with a decrease in LV mass indexed to body surface area and reduction in LV ejection fraction (also in men only). Hypertension-induced cardiac remodeling was linked to replacement fibrosis, diffuse fibrosis, and hypertrophy.
In this issue of iJACC, Yoneyama et al. (6) describe not only the associations among age, relevant cardiovascular information including risk factors, and LV structure and function, but interestingly also the associations among aging, changes to cardiovascular measures over a decade in the MESA cohort, and changes to CMR measures of cardiac structure and function. This study confirmed the findings of Eng et al. (3) that over a period of 10 years, LV end-diastolic volume and LV ejection fraction decreased, whereas LV mass and LV mass-to-volume ratio (a measure of concentric hypertrophy) increased. Using tagging CMR, they observed that longitudinally circumferential strain remained unchanged but that torsion increased. Increased LV mass, male sex, increased systolic blood pressure, increased heart rate, and reduced high-density lipoprotein cholesterol were associated with reduced circumferential strain. Individuals who remained on antihypertensive medications over the follow-up of 10 years maintained or improved circumferential strain. Yoneyama et al. (6) also found a “V-shaped” relationship between change in LV mass-to-volume ratio and torsion and concluded that increased torsion may be a mechanism to maintain LV systolic function as people get older. Sex affects the cardiac remodeling observed in MESA: effects are in opposing directions for LV mass (in men increases, in women decreases) and circumferential strain (in men decreases, in women increases). Effect direction is the same, but effect sizes differ by sex for LV end-diastolic volume (in women decreases more), LV mass-to-volume ratio (in men increases more), LV ejection fraction (in men decreases more), and torsion (in women increases more). The challenge posed by this paper by Yoneyama et al. (6) is to make sense of the data. MESA findings are becoming increasingly complex and thus are not always intuitive: for example, why are men and women different? Why is there a V-shaped relationship between torsion and concentric hypertrophy and what does it mean? The investigators offer attempts of explanations. Sex differences in cardiac remodeling may be related to differences in sex hormones. The initial increase in torsion with increased concentric hypertrophy may be due to subendocardial dysfunction with reduced endocardial opposition to the dominant epicardium. As the concentric remodeling progresses involving the entire thickness of the myocardium to become dysfunctional, this may then explain the reduced torsion.
As Nathaniel Reichek (7) pointed out in an editorial on a MESA publication, “Large sample sizes in multicenter studies combined with improved statistical methods have resulted in much greater ability to demonstrate statistically significant associations between variables.” Small effect sizes observed in MESA publications summarized in this editorial on assessing longitudinal changes in LV structure and function may allow the question of clinical significance of the findings. However, the mechanistic insights gleaned from these studies benefit from the greater precision of effect size estimates afforded by the large sample size. Cardiac remodeling can be assessed accurately and precisely by CMR, which provides promising surrogate markers for early phase clinical trials (8). However, they may even be useful to gain mechanistic insights in large-scale population-based studies as clinical “hard endpoints” of heart failure may not be frequent enough as demonstrated in this MESA paper by Yoneyama et al. (6) (only 28 participants had experienced incident heart failure and/or myocardial infarction over a decade). This lack of hard endpoints makes it difficult to answer questions about what these interesting and complex findings really mean for patients.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
This work forms part of the research contributing to the translational research portfolio of the Cardiovascular Biomedical Research Unit at Barts, which is supported and funded by the National Institute for Health Research. Prof. Petersen has received consultancy fees from Circle Cardiovascular Imaging.
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