Left Ventricular Hypertrophy Revisited
Cell and Matrix Expansion Have Disease-Specific Relationships
Left ventricular hypertrophy (LVH), a common pathway in health and disease, occurs because of cellular hypertrophy and expansion of extracellular matrix. Myocardial biopsy can identify extracellular matrix expansion (fibrosis, amyloid) from cellular hypertrophy and disarray and infiltration (iron, amyloid, inflammatory cells), but its invasive nature restricts its use to specific cases. Histology recognizes these cellular (cell death/hypertrophy) and extracellular matrix (fibrosis/infiltration) processes, but conventional cardiac imaging combines them into 1 compartment: the left ventricular mass (LVM).
Cardiovascular magnetic resonance (CMR) using T1 mapping can split LVM into cellular and matrix components by measuring the extracellular volume fraction (ECV). The cell volume is LVM/1.05×[1–ECV], and the matrix volume is LVM/1.05×ECV, 1.05 being the specific gravity of the myocardium. We used this approach to explore the biology of LVH.
The study was approved by the ethical committee of the UK National Research Ethics Service (07/H0715/101) and conformed to the principles of the Helsinki Declaration. All subjects gave written consent to participate; 190 subjects underwent CMR, including healthy volunteers (HV; n=30, male 44%, 41±11 years of age, no cardiovascular history, and normal ECG and CMR), and 160 subjects with LVH, defined as increased indexed LVM: athletes (AT; n=50, male 80%, 42±14 years of age, >10 endurance events in lifetime), severe aortic stenosis awaiting valve replacement (AS; n=30, male 66%, 74±6 years of age, aortic valve area indexed 0.4±0.1 cm2), Fabry disease (FD; n=20, male 75%, 51±9 years of age, gene-positive), hypertrophic cardiomyopathy (HCM; n=30, male 57%, 50±16 years of age, asymmetrical LVH excluding apical HCM), and cardiac amyloidosis (CA; n=30, all transthyretin amyloid, male 90%, 76±7 years of age). CMR was at 1.5 Tesla with T1 mapping using the Shortened MOdified Look-Locker Inversion recovery method1 before and after a 0.1 mmol/kg bolus of gadoterate meglumine (gadolinium-DOTA, marketed as Dotarem, Guerbet S.A.). Cardiac chamber volumes, LVM, and T1 maps were quantified using CVI42 (Circle Cardiovascular Imaging Inc.) with manual contouring.2 Patients with infarct-pattern late gadolinium enhancement were not included. ECV was derived from pre- and postcontrast short axis T1 maps and blood hematocrit. Matrix and cell volumes were calculated as described above.
LVM progressively increased from health (HV) and physiological hypertrophy (AT, AS) to pathological hypertrophy (HV<AT<AS<HCM<FD<CA, P<0.001). ECV was highest in cardiac amyloid (ECVCA=60.6±7.8%) and lowest in young athletes (ECVAT=26.2±2.7%), with increasing ECV from healthy volunteers (ECVHV=28.0±2.9%) to LVH pathologies (ECVAS=28.5±2.6%, ECVHCM=33.1±5.2%, and ECVFD=29.8±4.0%). Matrix volume, generally around a quarter of the myocardial volume, progressively increased from health to disease (HV<AT<AS<HCM<FD<CA, P<0.001) (Figure 1B). Cell volume also progressively increased, with the exception of CA, which, despite having the highest LVM, had a lower cell volume than all cohorts apart from HV (HV<CA<AT<AS<HCM<FD, P<0.001) (Figure 1B). For each etiology apart from CA, cell and matrix volumes correlated strongly (R2=0.6–0.8, all P<0.01; Figure 1B) but with slightly different regression slopes. Cell hypertrophy predominated in AT (slope <2.5), whereas matrix expansion was more dominant in the pathological hypertrophy (AS, FD, HCM) with a slope >2.5. In CA, LVM was predominantly driven by extracellular matrix expansion (slope <1). The regression slope for AT was significantly different than pathological hypertrophy (P=0.01), and CA was significantly different than all other groups (P<0.0001) using ANCOVA.
We conclude that, for most causes of LVH, on average there is a proportional increase in cellular and matrix components with 2 exceptions: physiological cell hypertrophy in AT (mainly cellular) and amyloidosis (almost exclusively matrix). Thus, ECV-derived volumes provide pathophysiological insights beyond quantifying the degree of hypertrophy. These results are, however, for the average of disease categories. Further intradisease work, and particularly longitudinal follow-up work, is needed.
By multiplying by LVM/1.05 (specific gravity for myocardial tissue is assumed as for normal tissue), we move ECV on from a percentage to a volume—providing whole heart quantification, unlike histology. However, it does not distinguish the cause of the matrix increase (fibrosis, amyloid, edema) or the cell type that is expanded, although this is assumed to be myocytes. Similarly, the qualitative nature of the fibrosis, its maturity, its tensile properties, and its collagen subtypes are not assessed. Capillary density and vasodilatation will also have a minor influence. In the future, the measurement of additional parameters will be needed to capture more facets of myocardial biology. Finally, although this CMR approach appears relatively new, we acknowledge the pioneering of Franz Schwarz and colleagues3 who, in 1978, used invasive biopsy to divide LVH into cellular and fibrotic components in aortic stenosis.
Thomas A. Treibel, PhD*
Rebecca Kozor, PhD*
Katia Menacho, MD
Silvia Castelletti, MD
Heerajnarain Bulluck, PhD
Stefania Rosmini, MD
Sabrina Nordin, MD
Viviana Maestrini, MD
Marianna Fontana, PhD
James C. Moon, MD
Sources of Funding
Drs Treibel and Fontana were supported by doctoral research fellowships from the National Institute of Health Research (DRF-2013-06-102) and the British Heart Foundation (FS/12/56/29723), respectively. Dr Moon is directly and indirectly supported by the University College London Hospitals’ National Institute of Health Research Biomedical Research Center and Biomedical Research Unit at Barts Hospital. Dr Kozor was sponsored by Heart Research Australia.
Circulation is available at http://circ.ahajournals.org.
- © 2017 American Heart Association, Inc.
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