Myocardial Extracellular Volume

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 67, NO. 15, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2015.12.072

EDITORIAL COMMENT

Myocardial Extracellular Volume Unifying Form and Function in Heart Failure With Preserved Ejection Fraction* Michael Salerno, MD, PHD,a,b Christopher M. Kramer, MDa

T

he prevalence of heart failure (HF) is ex-

increased E/e0 by Doppler has been used to identify

pected to increase by 46% from 2012 to 2013

elevated filling pressures, the correlation between

(1). Heart failure with preserved ejection

E/e 0 and invasively measured hemodynamics, partic-

fraction (HFpEF) accounts for between 30% to 50%

ularly in patients with preserved EF, is only modest.

of HF cases, depending on the analysis and specific

The gold standard for measuring diastolic filling

choice of ejection fraction (EF) cut-off, and continues

pressures remains invasive cardiac catheterization.

to increase in prevalence (2). Although HFpEF was

However, to fully characterize the pressure–volume

initially thought to result primarily from diastolic

relationship of the LV, high-fidelity conductance

dysfunction, the complexities and heterogeneity of

catheters are required that are not typically used in

HFpEF are only beginning to be elucidated. In clinical

standard clinical practice. Simultaneous pressure-

trials of HFpEF, approximately 30% of patients had

volume measurements of the LV can quantify a

normal diastolic function (3,4), whereas up to two-

number of diastolic functional parameters, including

thirds of patients with HFpEF may have impaired sys-

Tau ( s ), the time constant of pressure-decay during

tolic function as defined by reduced longitudinal

isovolumic relaxation that characterizes early dia-

strain (5). Furthermore, the precise definition of

stolic relaxation, and beta ( b ), the passive stiffness

HFpEF has been challenging, as clinical studies have

constant

used cut-offs for EF ranging from 40% to 50%. This

pressure–volume relationship.

which

characterizes

the

end-diastolic

heterogeneity in the underlying disease and its defi-

Alterations of the extracellular matrix including

nition may partially explain why effective evidence-

diffuse myocardial fibrosis contribute to the patho-

based therapies for HFpEF have remained elusive.

physiology of HFpEF (6,7). Interest is growing in using

Another significant challenge in making the diagnosis

the unique potential of cardiovascular magnetic reso-

is that no clinical marker, imaging marker, or

nance (CMR) to quantify diffuse myocardial fibrosis in

biomarker is highly sensitive or specific for the diag-

hypertensive heart disease and HFpEF (8–11). Recent

nosis of HFpEF. Thus, improved noninvasive charac-

developments in myocardial T 1 mapping have enabled

terization of HFpEF is sorely needed.

CMR to quantify expansion of the extracellular volume

One of the hallmarks of HF is an increase in left

(ECV), which may be due to inflammation, edema, or

ventricular (LV) diastolic filling pressures. Although

fibrosis (12). In HFpEF, diffuse fibrosis is likely the major culprit, although inflammation may play a role as well (7). It is important to realize that ECV is not a

*Editorials published in the Journal of the American College of Cardiology

biomarker that is specific for fibrosis, but is the per-

reflect the views of the authors and do not necessarily represent the

centage of the voxel that is occupied by the extracel-

views of JACC or the American College of Cardiology.

lular space, which includes both the plasma space and

Cardiovascular Division, Department of Medicine, and

the interstitium. As ECV is a relative metric, changes

Department of Radiology and Medical Imaging, University of Virginia

in the size of the intracellular space (i.e., myocyte

From the

a

Health System, Charlottesville, Virginia; and the

b

Department of

Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia. This paper has been funded by the National Institutes of Health (grants NIH K23 HL112910-01 to Dr. Salerno and U01HL11700601A1 to Dr. Kramer).

hypertrophy) relative to the extracellular space can also affect the CMR-derived ECV. One study demonstrated that patients with HFpEF with invasively confirmed elevation in pulmonary

Salerno and Kramer

JACC VOL. 67, NO. 15, 2016 APRIL 19, 2016:1826–8

Unifying Form and Function in HFpEF

capillary wedge pressure had a lower post-contrast T 1

measures of diastolic function (E/e 0 , E/A Ar-A [time

time corresponding with myocardial fibrosis (9).

difference between pulmonary vein atrial reversal

However, post-contrast T 1 times can be confounded

and mitral valve A-wave]). In the patients with ECV >

by factors including imaging time after contrast and

median, there was a significantly higher b, indicating

contrast dose (13). By measuring the T 1 of the

reduced compliance, whereas in patients with ECV <

myocardium and the blood pool before and after

median, there was an increased baseline arterial

injection of a gadolinium (Gd) contrast agent, one can

elastance and higher LV pressures with exercise and a

quantify the partition coefficient which is a ratio of

trend toward prolonged s (p ¼ 0.07), indicating

the Gd concentration in the myocardium to the Gd

impaired relaxation. ECV could thus provide infor-

concentration in the blood pool. By correcting this

mation independent from that of assessment of dia-

ratio for the effect of hematocrit, the ECV can be

stolic function by echocardiography. Furthermore,

quantified. A recent study by Su et al. (11) demon-

ECV is load-independent as compared with the

strated that patients with HFpEF had increased ECV

echocardiographic parameters of diastolic function

as compared with SHF and control subjects and

and likely reflects the chronic myocardial remodeling

demonstrated correlation between volumetric filling

characteristic of HFpEF.

rate and ECV. To date, no study has investigated the relationship of ECV with invasive hemodynamics.

The study has some limitations, the most prominent of which is the small sample size given the invasiveness of the P-V assessment. However, it adds

SEE PAGE 1815

to the growing evidence that ECV assessment by

In this issue of the Journal, Rommel et al. (14)

CMR provides unique information regarding the

evaluated the relationship between ECV measured

state of the extracellular space in HFpEF. This

by T 1 mapping in patients with HFpEF and invasively

information is complementary to measures of dia-

measured parameters of diastolic function derived

stolic function (15). Only standard echocardiographic

from pressure-volume loops acquired during basal

measurements of diastolic function were acquired,

conditions, hand-grip exercise, and transient pre-

and it is possible that more subtle metrics of cardiac

load reduction. From the invasive P-V loops, stiff-

performance, such as diastolic strain assessed by

ness constant ( b ), end-systolic elastance, time con-

CMR or echocardiography, could relate closely to

stant of active relaxation ( s ), arterial elastance, and

diastolic stiffness.

relation)

This study contributes to our understanding of the

response to physical exertion were derived. T 1 map-

role of ECV measurements in the phenotypic charac-

ping with ECV determination was performed using

terization of HFpEF and demonstrates that ECV

the Modified Look Locker technique with assessment

measured by CMR can be used to characterize

of native T1 (pre-contrast) and post-contrast T 1 ac-

myocardial stiffness, a metric that heretofore could

quired 15 min after Gd contrast. Regions of focal

only be assessed by high-fidelity invasive measure-

fibrosis were excluded from analysis. ECV was

ments. There is a growing body of published data

significantly higher in patients with HFpEF. ECV was

suggesting that ECV provides novel information in

highly correlated with the LV stiffness constant b

HFpEF and ultimately could guide selection of pa-

EDPVR

(end

diastolic

pressure-volume

(R ¼ 0.75) and was its only independent predictor in a 0

tients for novel-antifibrotic therapies. ECV could

multivariate model adjusting for E/e and LA volume

provide an important noninvasive imaging tool for

index. Interestingly there was a correlation between

further understanding the relationship between form

native T 1 time and s at exercise, but not with ECV,

and function in HFpEF.

reflecting the fact that fibrosis is likely more related to diastolic stiffness rather than impaired diastolic

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

relaxation. When the patients in the HFpEF group

Christopher

were divided into 2 groups on the basis of median

Center, University of Virginia Health System, 1215 Lee

ECV, there were no differences in baseline char-

Street, Box 800170, Charlottesville, Virginia 22908.

acteristics, exercise testing, or echocardiographic

E-mail: [email protected].

M.

Kramer,

Cardiovascular

Imaging

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KEY WORDS extracellular volume fraction, heart failure with preserved ejection fraction, magnetic resonance imaging, pressure-volume loops