Upload
others
View
0
Download
0
Embed Size (px)
Citation preview
Considerations for clinical trials targeting the myocardial interstitium
Gavin A. Lewis, MBChB;1,2 Susanna Dodd, PhD;3 Josephine H. Naish, PhD;1 Joseph Selvanayagam, DPhil;-4 Marc Dweck, PhD;5 Christopher A Miller, PhD.1,2,6
Word count: 7,492 (body text, references, figure legends)
Affiliations1. Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology,
Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
2. Manchester University NHS Foundation Trust, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK
3. Department of Biostatistics, University of Liverpool, Block F, Waterhouse Bld, 1-5 Brownlow Street, Liverpool, L69 3GL, UK
4. Flinders University of South Australia, Flinders Drive, Bedford Park, Adelaide, 5042, Australia
5. Centre for Cardiovascular Science, University of Edinburgh, Little France Crescent, EH16 4SB, UK
6. Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative Medicine, School of Biology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
Funding: Dr Miller is funded by a Clinician Scientist Award (CS-2015-15-003) from the National Institute for Health Research. Dr Dweck is supported by the BHF (FS/14/78/31020) and is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA).
DisclosuresThe views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
Address for correspondenceDr. Christopher A. Miller, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PLTelephone: 0044 161 291 2034. Fax: 0044 161 291 2389Email: [email protected]
1
Abstract
The myocardial interstitium has emerged as a potential therapeutic target, and as a biological
entity to improve risk stratification and better guide existing interventions. Clinical trials
focusing on the myocardial interstitium are required in order to establish causality and
improve patient outcomes. This review will discuss issues around clinical trials targeting the
myocardial interstitium, including antifibrotic therapies, efficacy outcome measurements,
mechanistic outcome measurements and mediation analysis, sample size, trial duration,
considerations for multicentre trials, stratifying trial recruitment according to the interstitium
and approaches to enrich recruitment, using examples of ongoing clinical trials.
Condensed Abstract
The myocardial interstitium has emerged as a potential therapeutic target, and as a biological
entity to improve risk stratification and better guide existing interventions. Clinical trials
focusing on the myocardial interstitium have the potential to improve patient outcomes. This
review will discuss issues around trials targeting the myocardial interstitium, using examples
of ongoing trials.
Main messages
The myocardial interstitium is a potential therapeutic target and a potential risk stratifier
that can guide interventions.
Clinical trials focusing on the myocardial interstitium are required in order to establish
causality and improve patient outcomes.
Cardiovascular magnetic resonance provides quantitative assessment of the myocardial
interstitium, and many other features of cardiovascular structure and function, thus can be
used to stratify recruitment and to evaluate efficacy and mechanism.
2
Key words
Myocardial interstitium, myocardial fibrosis, cardiovascular magnetic resonance, clinical
trials
Abbreviations
BNP – brain natriuretic peptide
CMR – cardiovascular magnetic resonance
ECM – extracellular matrix
ECV – extracellular volume
HF – heart failure
HFpEF – heart failure with preserved ejection fraction
LGE – late gadolinium enhancement
LV – left ventricle
RAAS – renin-angiotensin-aldosterone system
RCT – randomised controlled trial
3
Introduction
Over the past decade, observational data has demonstrated non-infarct focal and diffuse
myocardial fibrosis to be strongly associated with adverse prognosis across a range of
cardiovascular conditions (1-3).
The fibrotic response to injury and its clinical importance in other organs (cf. liver cirrhosis)
has been widely appreciated for decades (4). The pathophysiological relevance of the
myocardial interstitium in cardiovascular disease has also been recognised for many years (5).
Cardiovascular magnetic resonance (CMR) imaging, particularly the late gadolinium
enhancement (LGE) and extracellular volume (ECV) techniques, has more recently provided
unparalleled non-invasive access to the myocardial interstitium (6-8), which has allowed
observational cohort studies to be conducted at sufficient scale to demonstrate the clinical
implications of myocardial fibrosis. Thus the myocardial interstitium has emerged as a
potential therapeutic target, and as a biological entity to risk stratify patients and better guide
existing interventions.
Why are trials focusing on the myocardial interstitium required?
Clinical trials focusing on the myocardial interstitium are required for two reasons (Central
illustration):
1. To establish causality. Whilst observational data is useful, the association between
myocardial fibrosis and adverse cardiovascular outcomes does not establish causality.
This requires randomised controlled trials (RCT) to show: A) The efficacy of antifibrotic
agents to attenuate fibrosis formation/regress established fibrosis, and determine the
impact this has on other aspects of myocardial structure and function such as contractile
function, remodelling, arrhythmia burden and energetics; B) The clinical effectiveness of
4
antifibrotic agents to improve patient survival and reduce hospital admissions; and C) The
clinical effectiveness of risk stratification based on myocardial fibrosis.
2. To improve patient outcomes. The prognosis of many cardiovascular conditions, e.g. heart
failure (HF), remains unacceptably poor. Targeting novel pathophysiological mechanisms,
such as myocardial fibrosis, with new therapeutics agents, and using novel
pathophysiological mechanisms to better target existing interventions, are required.
Is the myocardial interstitium modifiable?
There is extensive preclinical data demonstrating that inhibition of pathways such as the
renin-angiotensin-aldosterone system (RAAS) and transforming growth factor (TGF)-β,
biological therapies such as CCN5 gene transfer, and exercise, significantly attenuate the
formation of non-infarct myocardial fibrosis (e.g. in remote myocardium in models of
myocardial infarction) and regress established myocardial fibrosis (e.g. in models of
hypertension, pressure overload, diabetes) (9-19). In these models, fibrosis inhibition is
associated with improved left ventricular function, reduced incidence of HF and arrhythmias,
and improved survival. Inhibition of factors that detrimentally affect the quality of the
extracellular matrix (ECM), such lysyl oxidase-like 2, an enzyme that catalyses crosslinking
of collagen to form bundles of collagen that are considerably stiffer than individual collagen
fibres, is also associated with improved LV function and reduced incidence of HF
preclinically (20).
Regression of established myocardial fibrosis with pharmacological RAAS inhibition is also
observed in humans. In studies by Izawa et al (in patients with dilated cardiomyopathy) (21),
Brilla et al (22), Schwartzkopff et al (23) and Diez et al (24) (all in hypertensive heart
disease), 6-12 months of RAAS inhibition was associated with significant, albeit modest,
5
reductions in histological collagen volume fraction measured from myocardial tissue obtained
at endomyocardial biopsy before and after treatment. Fibrosis regression was associated with
improvements in LV mechanical and microvascular function.
More recently, in studies using CMR ECV to measure ECM volume, Heydari et al
demonstrated a significant reduction in remote myocardial fibrosis formation with omega-3
fatty acid treatment following acute myocardial infarction (25), and Treibel et al showed
aortic valve replacement for aortic stenosis was associated with a significant reduction in
established diffuse myocardial fibrosis, which has been confirmed by Everett et al (26,27)
Antifibrotic drug therapies
In order to investigate the causal role of myocardial fibrosis in cardiovascular disease,
mechanistic trials of haemodynamically neutral therapies that also do not have a direct effect
on cardiomyocyte function are required (28). The beneficial effects of RAAS inhibition is
well recognised to extend beyond their haemodynamic impact, and it is widely hypothesised
that their antifibrotic effect is a key mechanism of their action, however, it is impossible to
separate their haemodynamic and anti-fibrotic effects. In this regard, pirfenidone, an
antifibrotic agent with proven clinical effectiveness in pulmonary fibrosis and which does not
have a haemodynamic effect, holds promise. The PIROUETTE trial (PIRfenidOne in patients
with heart failUre and preserved lEfT venTricular Ejection fraction; NCT02932566) is
evaluating the efficacy and safety of pirfenidone in patients with chronic heart failure and
preserved ejection fraction (HFpEF) and myocardial fibrosis (Figure 1).
A recent review by Li et al has comprehensively summarised existing drug therapies targeting
tissue fibrosis and those in development (29).
6
Phase II trial efficacy outcome measurements
ECV is a quantitative measurement of the myocardial interstitial space. Whilst the interstitium
includes other elements, such as capillaries and fluids, the primary interstitial structure is the
ECM, which is predominantly composed of collagen. There is a wealth of data to support
ECV as a robust measure of myocardial fibrosis in non-infarcted myocardium (7,30-35). ECV
is highly reproducible across separate CMR scans and can detect clinical reversal of
myocardial fibrosis (25,30,36-40). Crucially, ECV is clinically meaningful – it strongly
associates with adverse outcome, including death and heart failure admission, in large cohorts
of patients undergoing CMR scanning (2,41,42). As such, ECV is well suited as an outcome
measurement in phase II/experimental medicine trials evaluating the efficacy of interventions
aiming to attenuate myocardial fibrosis formation or regress established myocardial fibrosis.
ECV also allows quantitative measurement of absolute myocardial ECM mass (the product of
LV mass and ECV, which has been referred to as iECV and has also been expressed as a
volume (43)) and myocardial cellular mass (the product of LV mass and (1 – ECV)) (44). In
trials of interventions expected to lead to both cardiomyocyte and myocardial fibrosis
regression, it may be that absolute myocardial ECM mass is a more useful measurement of
fibrosis regression than ECV. For example, Treibel et al found ECV actually increased after
aortic valve replacement (AVR) for aortic stenosis (pre-AVR: 28.2 ± 2.9%; 1 year post-AVR:
29.9 ± 4.0%) (26). However, there was a substantial reduction in total LV mass (88 ± 26g/m2
to 71 ± 19g/m2), and therefore despite the increase in ECV, absolute myocardial ECM mass
reduced by 16%. Interventions that are designed to target one ‘compartment’, for example a
pure anti-fibrotic agent may be better assessed using ECV, in mechanistic studies it is
suggested that all parameters are measured.
7
Native myocardial T1 relaxation time also provides an assessment of myocardial fibrosis and
associates with adverse outcomes, and has a significant advantage over ECV in not requiring
gadolinium-based contrast agent administration (45,46). However, native T1 is not specific to
the interstitium, being also determined by cardiomyocyte characteristics, and as a result, the
correlation between native T1 and histological collagen volume fraction is less robust than for
ECV. Furthermore, native T1 is more dependent on field strength, sequence choice and
imaging parameters than ECV.
Whilst LGE is key for selecting patients for trial entry according the presence or absence of
focal non-infarct myocardial fibrosis (see ‘Stratifying trial recruitment according to the
myocardial interstitium’ below), and for excluding patients with confounding conditions (e.g.
amyloidosis), the utility of LGE as an outcome measurement for quantifying changes in non-
infarct myocardial fibrosis is less clear. LGE detection of fibrosis requires spatial
heterogeneity, thus it is not suitable for quantifying non-infarct myocardial fibrosis, indeed it
is not validated as a quantitative metric for this purpose (44,47).
Myocardial mechanical measurements (e.g. strain) are governed by multiple factors in
addition to myocardial fibrosis, such as cardiomyocyte function, myocardial ischaemia, and
loading conditions. Strain measurements therefore do not necessarily correlate with ECV, and
should not be considered surrogates for myocardial fibrosis. The limitations of circulating
biomarkers of collagen metabolism have been reviewed previously (48), but in brief, are not
cardiac specific and are influenced by comorbidities.
Mechanistic outcome measurements and mediation analysis
8
Determining the relationships between myocardial fibrosis and other aspects of myocardial
structure and function are important for understanding how myocardial fibrosis exerts a
deleterious effect, the mechanisms by which interventions that target the interstitium may
exert a beneficial effect, and, ultimately, for understanding myocardial pathophysiology in
general.
In preclinical studies, ‘pure’ antifibrotic interventions, i.e. without haemodynamic or direct
cardiomyocyte effects, are associated with improved LV systolic and diastolic function and
reduced incidence of arrhythmias (20,49-51). In the described human studies by Diez et al
(24), Brilla et al (22) and Izawa et al (21), myocardial fibrosis regression was associated with
reduced LV stiffness and improved diastolic function, although this association may be
confounded by the blood pressure lowering effect of the interventions. Human observational
data suggests associations between myocardial fibrosis and mechanical function, capillary
rarefaction and microvascular dysfunction, and arrhythmia (52-54).
Clinical trials of antifibrotic interventions will help establish causal relationships. Mediation
analysis, conducted as part of a trial, allows estimation of the direct and indirect (via a
mediator variable) effects of an intervention on outcome, and therefore may be used to
investigate the mechanistic pathways of trial interventions (Figure 2). For example, mediation
analysis can be used to determine whether a reduction in myocardial fibrosis (the putative
mediator variable) following an intervention causes change in myocardial mechanical
function, LV remodelling or arrhythmia burden (the outcome variables). The mediation
analysis adjusts for baseline covariates that predict both change in myocardial fibrosis and
outcome (e.g. mechanical function) and sensitivity analyses can be conducted to assess the
potential impact of unmeasured confounding between the mediator and outcome.
9
A widely held hypothesis is that ECM expansion impairs myocyte capillary blood supply,
which leads to cardiomyocyte energy starvation and impaired energetics. In a substudy of the
PIROUETTE trial, phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio will be
measured using 31phosphorus magnetic resonance spectroscopy in order to determine whether
myocardial fibrosis is leads to impaired energetics, assessed using mediation analysis (Figure
1).
Sample size considerations
A sample size calculation is required in order to determine the number of participants needed
to detect a clinically relevant treatment effect. In a two-arm superiority trial, which aims to
determine whether or not a true difference exists between the control and treatment groups,
the null hypothesis would be that there is no difference between treatments. If the observed
differences between treatment arms are large enough by chance alone, it is possible to reject
the null hypothesis incorrectly (Type I error (α) or a false positive result). Conversely, with
insufficient numbers, it is likely that that the null hypothesis will not be rejected even if it is
false (Type II error (β) or a false negative result). The sample size calculation imposes limits
on the probability of a Type I or Type II error occurring: typically a limit of 5% is imposed
for α and a limit of 10-20% is imposed for β. The power of the study (defined as the
probability that the study will reject the null hypothesis, i.e. conclude that there is a significant
difference between treatments, if such a treatment exists in reality) is equal to 100-β, therefore
the typical power of a study is 80-90%. The restrictions on the false positive rate are more
stringent than the false negative rate because of the relatively less important consequences of
failing to identify the superiority of a new treatment compared with changing practice to an
inferior treatment, if it is wrongfully concluded that the new treatment is superior (55).
10
Along with the limits for α and β, the sample size calculation requires estimates of the
minimum clinically important difference (MCID) that the new treatment must demonstrate in
order to justify the use of the treatment in practice, and an estimate of the precision with
which the primary outcome measurement is measured in the population being studied i.e. a
measure of its variability in this population.
The MCID is a clinical decision that is often poorly justified in clinical trials in general (56).
One reason for this is that the magnitude of the change in phase II end points expected to
translate into improved clinical outcomes at phase III is often challenging to determine. As
described by Butler et al (57), while phase II endpoints for lipid and blood pressure
modulating interventions are relatively straightforward, achieving the prescribed phase II
MCID does not necessarily translate into improved patient outcome (58). Clinically
meaningful phase II endpoints for trials in other cardiovascular conditions, such as HF, have
proven even more challenging to identify and apply (57). For example, whilst the prognostic
utility of natriuretic peptides is well established, interventions associated with improvements
in natriuretic peptide levels at phase II have often not translated into improved clinical
outcomes at phase III, indeed natriuretic peptide-guided care has not proven to be clinically
effective (59).
A potential reason for the lack of ‘translatability’ of natriuretic peptides is that they are not
reflective of specific pathophysiological mechanisms, and therefore do not provide feedback
on whether or not an intervention has modulated the mechanism it was designed to target.
Conversely, ECV is directly reflective of the myocardial fibrotic process and thus has the
potential to be a more effective phase II endpoint.
11
In a study by Schelbert et al in patients with HFpEF or at risk of HFpEF, a 2% increase in
ECV was associated with a 21% increased risk of clinical adverse outcome (combined end
point of death or hospitalisation for HF) over a median follow-up period of 1.9 years (41).
Thus, this degree of change in ECV, for example, appears to be clinically meaningful.
Regarding estimates of the precision of ECV, natural history studies evaluating longitudinal
changes in ECV, and hence reporting the associated within-patient variability, have been
published in relatively few cardiovascular disease areas. In patients with acute myocardial
infarction, Bulluck et al, who scanned 50 patients at 4 ± 2 days and again at 5 ± 2 months
post-MI, found the standard deviation of within-patient difference in remote myocardial ECV
to be 1.9% (60). Similarly Carberry et al, who scanned 140 patients at 2.3 ± 1.9 days and 6
months post-MI found the standard deviation of within-patient difference in remote
myocardial ECV to be 2.6% (61). In a study by Garg et al, who scanned patients with type II
diabetes before and after 6 months of spironolactone or hydrochlorothiazide, the standard
deviation of within-patient difference in myocardial ECV in the placebo group was 3% (62).
In a study by Everett et al that included a natural history cohort, 61 asymptomatic patients
with aortic stenosis (43% mild, 34% moderate, 23% severe) underwent CMR at baseline and
again 2.1±0.7 years later. The interquartile range of the annualised within-patient difference in
myocardial ECV was -1 to 1%, and the annualised within-patient difference in absolute ECM
volume was 0 to 2.3 ml/m2 (27). Natural history studies in more disease areas are required.
An example sample size calculation for a phase II parallel group, 1:1 randomised placebo-
controlled trial of an antifibrotic drug, using change in ECV as the primary outcome measure,
would be as follows: Using a standard deviation of within-patient differences in ECV from
12
baseline of 3% in both groups, 37 patients per group would be required to detect a minimum
difference, between active drug and placebo groups, of 2% in terms of change ECV from
baseline following a period of treatment, with 80% power at a 5% (α) significance level (2-
sided).
Trial duration
The optimal duration for phase II trials investigating antifibrotic interventions seems likely to
depend on whether the aim of the trial is to attenuate myocardial fibrosis formation, for
example fibrosis formation in remote myocardium following myocardial infarction, or to
regress established myocardial fibrosis, for example in aortic stenosis or HFpEF.
Following a myocardial infarction, TGF-β is elevated in remote myocardium from day 1,
peaking at around day 3 to 7 in preclinical models (63). Remote myocardial collagen
accumulation is seen to begin at day 3. In trials demonstrating clinical benefit of RAAS
inhibition in this context, therapy was generally started at days 1-14 post-myocardial
infarction, although there may be greater benefit with initiation earlier in this period (64). The
majority of remodelling, as assessed using LV volumetrics, occurs within the first 3 months
post-myocardial infarction, and early trials of angiotensin converting enzyme inhibitors post-
myocardial infarction found only 4-6 weeks of treatment was associated with significant
reductions in HF and death (65-68). Therefore when designing, for example, a phase II trial
aimed at attenuating remote myocardial fibrosis formation post-myocardial infarction,
initiating treatment early post-myocardial infarction may be associated with maximal benefit,
and a treatment duration of 3 months may be sufficient.
13
In the previously described histological studies demonstrating regression of established
myocardial fibrosis with RAAS inhibition in humans, significant fibrosis regression was
observed with 6 months of treatment (Brilla et al (22): 9% relative percentage reduction in
collagen volume fraction), but a larger effect was observed in the studies where treatment
duration was 12 months (Izawa et al (21): approximately 28% reduction; Schwartzkopff et
al(23): 22% reduction; Diez et al (24): 14% reduction). In the aforementioned study by
Treibel et al demonstrating a reduction in absolute myocardial ECM mass measured using
CMR following AVR for aortic stenosis, the follow-up CMR was performed at 12 months
post-AVR (26). Therefore when designing a phase II trial aimed at regressing established
myocardial fibrosis, a treatment duration of 6 – 12 months may be required.
Considerations for multicentre trials
The inclusion of a quantitative imaging biomarker such as ECV in a multicentre trial setting
creates some particular issues with regards to the consistency of results across centres.
Different institutions will typically have access to scanners from different vendors and field
strengths, which may be broadly similar in terms of clinical radiology capability, but which
can have significant differences in terms of T1 quantitation. Prior to commencing a
multicentre trial, acquisition protocols should be standardised for each scanner vendor and
field strength and, as much as possible, harmonised across vendors.
A site qualification process can help to ensure conformance to a consistent protocol across
participating sites. This will generally include an initial technical survey to assess MRI
hardware and software capabilities, followed by a site training session in which the protocol is
implemented at the site, and phantom and possibly also healthy volunteer data are acquired.
T1 phantoms that encompass the range of pre- and post-contrast T1 values expected (such as
14
the T1MES phantom (69)) allow some assessment of ECV accuracy and precision. Once a
site has been qualified and entered into the trial, a centralised ongoing site quality assurance
can help to identify and rectify any issues as they arise. Since ECV is calculated as a ratio, it
is inherently more robust to systematic measurement errors than native T1, but regular on-
going acquisition of phantom data can help to detect any drift or step changes that may occur
as a result of software or hardware upgrade or failure.
While some degree of variability in the acquired pre- and post-contrast T1 data may be
inevitable across sites in a multicentre trial, it is possible to avoid additional variability due to
the post processing steps by using a single site for centralised image analysis. Centralised
analysis allows for a defined image analysis pipeline following standard operating procedures
using trained image readers and enables a clear analysis audit trail, but raises additional
considerations around secure data transfer and management of the central analysis site.
Remaining inter-site variability in the assessment of ECV, due to the variability in the
acquired data, may in part be accounted for in the statistical analysis, including stratification
of randomisation by site.
Stratifying trial recruitment according to the myocardial interstitium
Interventions may have more benefit, or may only be beneficial, in groups of patients with
certain pathophysiological characteristics. For example, in the aforementioned studies by
Izawa et al and Diez et al (21,24), significant fibrosis regression with RAAS inhibition was
confined, perhaps intuitively, to patients with a higher burden of fibrosis at baseline.
Similarly, in a subgroup analysis of the Randomized Aldactone Evaluation Study (RALES)
15
study, Zannad et al found the prognostic benefit of spironolactone was limited to those
patients with elevated baseline circulating collagen synthesis biomarkers (70).
Predictive enrichment trials select patients according to distinctive individual characteristics
in order to target those patients who are thought more likely to benefit from the intervention
(Table 1). The on-going EVoLVeD (Early Valve Replacement guided by Biomarkers of Left
Ventricular Decompensation in Asymptomatic Patients with Severe Aortic Stenosis;
NCT03094143; Figure 3) and CMR GUIDE (Cardiovascular magnetic resonance-GUIDEd
management of mild to moderate left ventricular systolic dysfunction; NCT01918215; Figure
4) trials are selecting patients according to the presence of focal replacement myocardial
fibrosis, as assessed using CMR LGE. The PIROUETTE trial is selecting patients according
to myocardial fibrosis burden, measured using CMR ECV (Figure 1).
EVoLVeD
Myocardial fibrosis is a key driver of left ventricular decompensation in aortic stenosis and
the transition from hypertrophy to HF (71). Replacement myocardial fibrosis can be imaged
using LGE and observed in a non-ischemic pattern. Recent studies have demonstrated that
non-ischemic LGE progresses rapidly once developed and that it is irreversible following
AVR. This is important because such fibrosis is associated with an adverse prognosis. Indeed
multiple independent studies have confirmed that non-ischemic LGE in patients with aortic
stenosis acts as an objective biomarker of LV decompensation and is a powerful independent
predictor of long-term outcomes (3,72,73). In the study by Musa et al, LGE was a powerful
independent predictor of all-cause (26.4% vs. 12.9%; p<0.001) and cardiovascular mortality
(15.0% vs. 4.8%; p<0.001) in patients with severe AS imaged just prior to AVR (3).
Furthermore, this association appeared dose-dependent: with every 1% increase in LV LGE
16
burden, all-cause mortality increased by 11% (hazard ratio (HR) 1.11, 95% confidence
intervals (CI) 1.05-1.17, p<0.001).
This data provides the rationale for the EVOLVED trial. It is a multicentre randomised
controlled trial investigating whether early surgery in asymptomatic patients with severe
aortic stenosis and evidence of replacement myocardial fibrosis (i.e. presence of non-infarct
LGE on CMR) improves clinical outcomes compared to the standard approach of watchful
waiting. Patients undergo a CMR as part of the baseline assessment and those patients with
evidence of replacement myocardial fibrosis are randomised into the full study.
CMR GUIDE
There is clear pre-clinical and clinical evidence that myocardial fibrosis forms the critical
mechanical substrate for ventricular arrhythmias, a common cause of sudden cardiac death
(SCD) in patients with heart disease. As there was previously no direct method to visualise
myocardial fibrosis, LV EF was used as a surrogate for fibrosis burden, and for predicting the
patients most at risk for SCD. Accordingly current international guidelines assign a class I
recommendation for implantable cardioverter defibrillator (ICD) implantation for primary
prevention of SCD in patients with a LVEF ≤ 35% on optimal medical therapy (74).
However, recent studies highlight that these guidelines substantially underestimate the
number of patients who would benefit from ICD implantation (75). The majority of SCD
occurs in patients with mildly impaired or preserved LVEF (76,77), a trend reflected in both
historic and contemporary data, indicating that LVEF is an imperfect surrogate of myocardial
fibrosis and that current risk stratification in patients with a LVEF above 35% are suboptimal.
17
The CMR Guide trial is a international, multicentre, combined registry and randomised trial
evaluating the effectiveness of ICD therapy in patients with mild-moderately reduced LV EF
and focal replacement myocardial fibrosis detected on LGE imaging in preventing SCD or
haemodynamically significant ventricular arrhythmia (78). Patients with mild-moderately
reduced LV EF undergo baseline CMR and those that demonstrate LGE are randomised to
implantation of either ICD or implantable loop recorder. Investigators hypothesise that among
patients with mild-moderately reduced LV EF, a CMR-guided management strategy for ICD
implantation based on the presence of focal replacement fibrosis will be superior to a current
standard care. A T1 mapping/ECV substudy will assess the relationship between baseline
ECV and arrhythmic events.
PIROUETTE
Schelbert et al, and others, have shown myocardial fibrosis burden, measured using ECV, is
strongly and independently associated with adverse outcome in patients with heart failure
with preserved ejection fraction (HFpEF) or at risk for HFpEF (41). Whilst myocardial
fibrosis is consistently demonstrated on a group level in patients with HFpEF, it is not
universal, with approximately one-third to one-half of patients having normal measures of
myocardial fibrosis (41,79,80).
In the PIROUETTE trial, eligible patients undergo a baseline CMR scan and only those with
evidence of myocardial fibrosis, as determined by a pre-specified ECV threshold, undergo
randomisation. Those that do not have myocardial fibrosis at baseline enter a registry.
Such personalised medicine approaches, based on individual biological phenotypes, are
consistent with the widely held aim among research funders, deliverers of medical research
18
and delivers of healthcare, of providing ‘the right intervention to the right patient at the right
time’. These trials also serve to demonstrate the utility of the deep phenotyping provided by
contemporary cardiovascular imaging.
Yet, these precision medicine approaches come with a cost. In each of the described trials a
substantially greater number of patients are required to undergo baseline CMR than will be
randomised. For example, in CMR GUIDE, it is estimated that, after accounting for 10% drop
out, 949 patients will be required to undergo baseline CMR in order to identify 428 patients
with evidence of myocardial fibrosis i.e. 521 (55%) patients will undergo CMR but will not
be randomised (78). It is important that research funders recognise the extra (short-term)
funding, and time, required to deliver personalised research. Targeting patients based on their
individual pathophysiology intuitively should translate into a higher chance of finding clinical
benefit, hence this approach has the potential for substantial long-term research and clinical
cost savings.
Approaches to enrich recruitment
A cost-effective solution to this problem is to screen patients as having a higher or lower
probability of myocardial fibrosis using cheaper and easily accessible biomarkers. In aortic
stenosis high sensitivity troponin I (hsTnI) has emerged as a sensitive, marker of left
ventricular decompensation and prognostic marker. Patients with a troponin <6ng/L have a
low probability of myocardial fibrosis and a good prognosis (81). In the EVOLVED trial
troponin is therefore being used a screening tool to select patients that should proceed to
CMR imaging. Patients with a normal troponin <6ng/L are considered to have a healthy
myocardium and therefore are kept under routine follow up. Patients with an elevated
19
troponin proceed to CMR and if non-infarct LGE is identified are then randomised either to
early valve replacement or the routine approach of watchful waiting.
Similarly, Schelbert et al found myocardial fibrosis, measured using ECV, was strongly
associated with brain natriuretic peptide (BNP) in patients with, and at risk of, HFpEF (41).
Thus BNP could be used to identify patients who are more likely to have an elevated ECV on
CMR.
Conclusions and outlook
Personalised approaches, based on prognostically important pathophysiological mechanisms,
are required in order to improve our rate of positive phase III trials. Myocardial fibrosis, an
example of such a mechanism, has the potential to improve risk stratification, guide care more
precisely and be a therapeutic target. The results of the discussed trials are eagerly awaited.
CMR provides tools to conduct trials that focus on the myocardial interstitium. A single CMR
exam can be used to identify individual patients according to their fibrotic burden, directly
measure the antifibrotic effect of interventions targeting the interstitium rather than non-
mechanism discriminant indirect measurements such as natriuretic peptides and exercise
tolerance, and provide a range of other measurements of myocardial structure and function to
determine the impact of interstitial modulation.
In these regards, CMR has the potential to become a highly valuable resource for evaluating
the efficacy, mechanisms of action and safety of new or repurposed drugs. However, fulfilling
this potential requires standardisation across vendors. Current vendor differences in hardware
and software are undoubtedly holding the CMR field back, to the considerable detriment of
20
the CMR field, the pharmaceutical industry, investigators, vendors, and ultimately, our
patients.
Circulating biomarkers that are specific to the structure and function of myocardial
interstitium, which would be more widely applicable, simpler and likely cheaper than CMR,
are highly desirable. Therapeutics that target the myocardial interstitium are also required.
21
References
1. Gulati A, Jabbour A, Ismail TF et al. Association of fibrosis with mortality and sudden
cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA
2013;309:896-908.
2. Wong TC, Piehler KM, Kang IA et al. Myocardial extracellular volume fraction
quantified by cardiovascular magnetic resonance is increased in diabetes and associated
with mortality and incident heart failure admission. European heart journal 2014;35:657-
64.
3. Musa TA, Treibel TA, Vassiliou VS et al. Myocardial Scar and Mortality in Severe
Aortic Stenosis. Circulation 2018;138:1935-1947.
4. Longo DL, Rockey DC, Bell PD, et al. Fibrosis — A Common Pathway to Organ Injury
and Failure. NEJM 2015;372:1138-1149.
5. Weber KT. Cardiac interstitium in health and disease: the fibrillar collagen network.
Journal of the American College of Cardiology 1989;13:1637-52.
6. Azevedo CF, Nigri M, Higuchi ML et al. Prognostic significance of myocardial fibrosis
quantification by histopathology and magnetic resonance imaging in patients with severe
aortic valve disease. Journal of the American College of Cardiology 2010;56:278-87.
7. Flett AS, Hayward MP, Ashworth MT et al. Equilibrium contrast cardiovascular
magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary
validation in humans. Circulation 2010;122:138-144.
8. Miller CA, Naish JH, Bishop P et al. Comprehensive Validation of Cardiovascular
Magnetic Resonance Techniques for the Assessment of Myocardial Extracellular
Volume. Circulation: Cardiovascular Imaging 2013;6:373-383.
22
9. Okada H, Takemura G, Kosai K-i et al. Postinfarction gene therapy against transforming
growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular
remodeling and heart failure. Circulation 2005;111:2430-2437.
10. Tan SM, Zhang Y, Connelly KA, et al. Targeted inhibition of activin receptor-like kinase
5 signaling attenuates cardiac dysfunction following myocardial infarction. Am J Physiol
2010;298:H1415-H1425.
11. Hafstad AD, Lund J, Hadler-Olsen E, et al. High- and moderate-intensity training
normalizes ventricular function and mechanoenergetics in mice with diet-induced obesity.
Diabetes 2013;62:2287-94.
12. Jeong D, Lee MA, Li Y et al. Matricellular Protein CCN5 Reverses Established Cardiac
Fibrosis. Journal of the American College of Cardiology 2016;67:1556-1568.
13. Kolkhof P, Delbeck M, Kretschmer A et al. Finerenone, a novel selective nonsteroidal
mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc
Pharmacol 2014;64:69-78.
14. Sabbah HN, Gupta RC, Kohli S et al. Chronic therapy with a partial adenosine A1-
receptor agonist improves left ventricular function and remodeling in dogs with advanced
heart failure. Circulation Heart failure 2013;6:563-71.
15. Samuel CS, Hewitson TD, Zhang Y, et al. Relaxin ameliorates fibrosis in experimental
diabetic cardiomyopathy. Endocrinology 2008;149:3286-93.
16. Silva JA, Jr., Santana ET, Manchini MT et al. Exercise training can prevent cardiac
hypertrophy induced by sympathetic hyperactivity with modulation of kallikrein-kinin
pathway and angiogenesis. PLoS One 2014;9:e91017.
17. Esposito CT, Varahan S, Jeyaraj D, et al. Spironolactone improves the arrhythmogenic
substrate in heart failure by preventing ventricular electrical activation delays associated
23
with myocardial interstitial fibrosis and inflammation. Journal of cardiovascular
electrophysiology 2013;24:806-12.
18. von Lueder TG, Wang BH, Kompa AR et al. The Angiotensin-Receptor Neprilysin
Inhibitor LCZ696 Attenuates Cardiac Remodeling and Dysfunction After Myocardial
Infarction by Reducing Cardiac Fibrosis and Hypertrophy. Circulation Heart failure 2014.
19. Suematsu Y, Miura S, Goto M et al. LCZ696, an angiotensin receptor-neprilysin
inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with
reduced ejection fraction in streptozotocin-induced diabetic mice. Eur J Heart Fail
2016;18:386-93.
20. Yang J, Savvatis K, Kang JS et al. Targeting LOXL2 for cardiac interstitial fibrosis and
heart failure treatment. Nature communications 2016;7:13710.
21. Izawa H, Murohara T, Nagata K et al. Mineralocorticoid receptor antagonism ameliorates
left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic
patients with idiopathic dilated cardiomyopathy: a pilot study. Circulation
2005;112:2940-5.
22. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in
patients with hypertensive heart disease. Circulation 2000;102:1388-93.
23. Schwartzkopff B, Brehm M, Mundhenke M, et al. Repair of coronary arterioles after
treatment with perindopril in hypertensive heart disease. Hypertension 2000;36:220-5.
24. Diez J, Querejeta R, Lopez B, et al. Losartan-dependent regression of myocardial fibrosis
is associated with reduction of left ventricular chamber stiffness in hypertensive patients.
Circulation 2002;105:2512-7.
25. Heydari B, Abdullah S, Pottala JV et al. Effect of Omega-3 Acid Ethyl Esters on Left
Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL
Randomized Clinical Trial. Circulation 2016;134:378-391.
24
26. Treibel TA, Kozor R, Schofield R et al. Reverse Myocardial Remodeling Following
Valve Replacement in Patients With Aortic Stenosis. Journal of the American College of
Cardiology 2018;71:860-871.
27. Everett RJ, Tastet L, Clavel MA et al. Progression of Hypertrophy and Myocardial
Fibrosis in Aortic Stenosis: A Multicenter Cardiac Magnetic Resonance Study.
Circulation Cardiovascular imaging 2018;11:e007451.
28. Vaduganathan M, Butler J, Pitt B, et al. Contemporary Drug Development in Heart
Failure: Call for Hemodynamically Neutral Therapies. Circ: Heart Fail 2015;8:826-831.
29. Li X, Zhu L, Wang B, et al. Drugs and Targets in Fibrosis. Frontiers in pharmacology
2017;8:855.
30. Fontana M, White SK, Banypersad SM et al. Comparison of T1 mapping techniques for
ECV quantification. Histological validation and reproducibility of ShMOLLI versus
multibreath-hold T1 quantification equilibrium contrast CMR. Journal of cardiovascular
magnetic resonance. 2012;14:88.
31. White SK, Sado DM, Fontana M et al. T1 mapping for myocardial extracellular volume
measurement by CMR: bolus only versus primed infusion technique. JACC
Cardiovascular imaging 2013;6:955-62.
32. aus dem Siepen F, Buss SJ, Messroghli D et al. T1 mapping in dilated cardiomyopathy
with cardiac magnetic resonance: quantification of diffuse myocardial fibrosis and
comparison with endomyocardial biopsy. Eur Heart J Cardiovasc Imaging 2015;16:210-
6.
33. de Meester de Ravenstein C, Bouzin C, et al. Histological Validation of measurement of
diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from
Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T. J Cardiovasc Magn Reson
2015;17:48.
25
34. Inui K, Tachi M, Saito T et al. Superiority of the extracellular volume fraction over the
myocardial T1 value for the assessment of myocardial fibrosis in patients with non-
ischemic cardiomyopathy. Magn Reson Imaging 2016;34:1141-5.
35. Zeng M, Zhang N, He Y et al. Histological validation of cardiac magnetic resonance T1
mapping for detecting diffuse myocardial fibrosis in diabetic rabbits. Journal of magnetic
resonance imaging : JMRI 2016;44:1179-1185.
36. Schelbert EB, Testa SM, Meier CG et al. Myocardial extravascular extracellular volume
fraction measurement by gadolinium cardiovascular magnetic resonance in humans: slow
infusion versus bolus. Journal of cardiovascular magnetic resonance : official journal of
the Society for Cardiovascular Magnetic Resonance 2011;13:16.
37. Kawel N, Nacif M, Zavodni A et al. T1 mapping of the myocardium: intra-individual
assessment of post-contrast T1 time evolution and extracellular volume fraction at 3T for
Gd-DTPA and Gd-BOPTA. Journal of cardiovascular magnetic resonance : official
journal of the Society for Cardiovascular Magnetic Resonance 2012;14:26.
38. Chin CW, Semple S, Malley T et al. Optimization and comparison of myocardial T1
techniques at 3T in patients with aortic stenosis. Eur Heart J Cardiovasc Imaging
2014;15:556-65.
39. McDiarmid AK, Swoboda PP, Erhayiem B et al. Single bolus versus split dose
gadolinium administration in extra-cellular volume calculation at 3 Tesla. J Cardiovasc
Magn Reson 2015;17:6.
40. Singh A, Horsfield MA, Bekele S, et al. Myocardial T1 and extracellular volume fraction
measurement in asymptomatic patients with aortic stenosis: reproducibility and
comparison with age-matched controls. Eur Heart J Cardiovasc Imaging 2015;16:763-70.
26
41. Schelbert EB, Fridman Y, Wong TC et al. Temporal Relation Between Myocardial
Fibrosis and Heart Failure With Preserved Ejection Fraction: Association With Baseline
Disease Severity and Subsequent Outcome. JAMA cardiology 2017.
42. Schelbert EB, Piehler KM, Zareba KM et al. Myocardial Fibrosis Quantified by
Extracellular Volume Is Associated With Subsequent Hospitalization for Heart Failure,
Death, or Both Across the Spectrum of Ejection Fraction and Heart Failure Stage. Journal
of the American Heart Association 2015;4:e002613-14.
43. Chin CWL, Everett RJ, Kwiecinski J et al. Myocardial Fibrosis and Cardiac
Decompensation in Aortic Stenosis. JACC Cardiovascular imaging 2017;10:1320-1333.
44. Messroghli DR, Moon JC, Ferreira VM et al. Clinical recommendations for
cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: A
consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR)
endorsed by the European Association for Cardiovascular Imaging (EACVI). 2017:1-24.
45. Bull S, White SK, Piechnik SK et al. Human non-contrast T1 values and correlation with
histology in diffuse fibrosis. Heart 2013;99:932-7.
46. Puntmann VO, Carr-White G, Jabbour A et al. Native T1 and ECV of Noninfarcted
Myocardium and Outcome in Patients With Coronary Artery Disease. Journal of the
American College of Cardiology 2018;71:766-778.
47. Flett AS, Hasleton J, Cook C et al. Evaluation of techniques for the quantification of
myocardial scar of differing etiology using cardiac magnetic resonance. JACC
Cardiovascular imaging 2011;4:150-6.
48. Lopez B, Gonzalez A, Ravassa S et al. Circulating Biomarkers of Myocardial Fibrosis:
The Need for a Reappraisal. Journal of the American College of Cardiology
2015;65:2449-56.
27
49. Li C, Han R, Kang L et al. Pirfenidone controls the feedback loop of the AT1R/p38
MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial
infarction-induced cardiac fibrosis. Scientific Reports 2017:7; doi: 10.1038/srep40523.
50. Nguyen DT, Ding C, Wilson E, et al. Pirfenidone mitigates left ventricular fibrosis and
dysfunction after myocardial infarction and reduces arrhythmias. HRTHM 2010;7:1438-
1445.
51. Thum T, Gross C, Fiedler J et al. MicroRNA21 contributes to myocardial disease by
stimulating MAP kinase signalling in fibroblasts. Nature 2008;456:980-984.
52. Garg P, Broadbent DA, Swoboda PP et al. Extra-cellular expansion in the normal, non-
infarcted myocardium is associated with worsening of regional myocardial function after
acute myocardial infarction. Journal of cardiovascular magnetic resonance : official
journal of the Society for Cardiovascular Magnetic Resonance 2017;19:1-13.
53. Mohammed SF, Hussain S, Mirzoyev SA, et al. Coronary microvascular rarefaction and
myocardial fibrosis in heart failure with preserved ejection fraction. Circulation
2015;131:550-9.
54. Tamarappoo BK, John BT, Reinier K et al. Vulnerable myocardial interstitium in patients
with isolated left ventricular hypertrophy and sudden cardiac death: a postmortem
histological evaluation. J Am Heart Assoc 2012;1:e001511.
55. Machin D, Campbell MJ, Tan SB, et al. Sample size tables for clinical, laboratory and
epidemiology studies, 4th Edition.Wiley-Blackwell, 2018.
56. Cook JA, Hislop J, Altman DG et al. Specifying the target difference in the primary
outcome for a randomised controlled trial: guidance for researchers. Trials 2015;16:12.
57. Butler J, Hamo CE, Udelson JE et al. Reassessing Phase II Heart Failure Clinical Trials:
Consensus Recommendations. Circ Heart Fail 2017;10.
28
58. Barter PJ, Caulfield M, Eriksson M et al. Effects of torcetrapib in patients at high risk for
coronary events. N Engl J Med 2007;357:2109-22.
59. Felker GM, Anstrom KJ, Adams KF et al. Effect of Natriuretic Peptide-Guided Therapy
on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure
and Reduced Ejection Fraction: A Randomized Clinical Trial. Jama 2017;318:713-720.
60. Bulluck H, Rosmini S, Abdel-Gadir A et al. Automated Extracellular Volume Fraction
Mapping Provides Insights Into the Pathophysiology of Left Ventricular Remodeling
Post–Reperfused ST‐Elevation Myocardial Infarction. Journal of the American Heart
Association 2016;5:1-11.
61. Carberry J, Carrick D, Haig C et al. Remote Zone Extracellular Volume and Left
Ventricular Remodeling in Survivors of ST-Elevation Myocardial Infarction.
Hypertension 2016;68:385-91.
62. Garg R, Rao AD, Baimas-George M et al. Mineralocorticoid Receptor Blockade
Improves Coronary Microvascular Function in Individuals With Type 2 Diabetes.
Diabetes 2014;64:236-242.
63. Tsuda T, Gao E, Evangelisti L, et al. Post-ischemic myocardial fibrosis occurs
independent of hemodynamic changes. Cardiovascular research 2003;59:926-33.
64. Adamopoulos C, Ahmed A, Fay R et al. Timing of eplerenone initiation and outcomes in
patients with heart failure after acute myocardial infarction complicated by left
ventricular systolic dysfunction: insights from the EPHESUS trial†. European Journal of
Heart Failure 2009;11:1099-1105.
65. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction:
pathophysiology and therapy. Circulation 2000;101:2981-8.
29
66. Li X, Qi Y, Li Y et al. Impact of mineralocorticoid receptor antagonists on changes in
cardiac structure and function of left ventricular dysfunction: a meta-analysis of
randomized controlled trials. Circulation: Heart Failure 2013;6:156-165.
67. GISSI-3. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and
together on 6-week mortality and ventricular function after acute myocardial infarction.
Lancet 1994;343:1115-22.
68. ISIS-4. ISIS-4: a randomised factorial trial assessing early oral captopril, oral
mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected
acute myocardial infarction. Lancet 1995;345:669-85.
69. Captur G, Gatehouse P, Keenan KE et al. A medical device-grade T1 and ECV phantom
for global T1 mapping quality assurance-the T1 Mapping and ECV Standardization in
cardiovascular magnetic resonance (T1MES) program. J Cardiovasc Magn Reson
2016;18:58.
70. Zannad F, Alla F, Dousset B, et al. Limitation of Excessive Extracellular Matrix
Turnover May Contribute to Survival Benefit of Spironolactone Therapy in Patients With
Congestive Heart Failure : Insights From the Randomized Aldactone Evaluation Study
(RALES). Circulation 2000;102:2700-2706.
71. Hein S, Arnon E, Kostin S et al. Progression from compensated hypertrophy to failure in
the pressure-overloaded human heart: structural deterioration and compensatory
mechanisms. Circulation 2003;107:984-91.
72. Dweck MR, Joshi S, Murigu T et al. Midwall fibrosis is an independent predictor of
mortality in patients with aortic stenosis. Journal of the American College of Cardiology
2011;58:1271-9.
73. Weidemann F, Herrmann S, Stork S et al. Impact of myocardial fibrosis in patients with
symptomatic severe aortic stenosis. Circulation 2009;120:577-84.
30
74. Russo AM, Stainback RF, Bailey SR et al.
ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for
implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of
the American College of Cardiology Foundation appropriate use criteria task force, Heart
Rhythm Society, American Heart Association, American Society of Echocardiography,
Heart Failure Society of America, Society for Cardiovascular Angiography and
Interventions, Society of Cardiovascular Computed Tomography, and Society for
Cardiovascular Magnetic Resonance. Journal of the American College of Cardiology
2013;61:1318-68.
75. Dagres N, Hindricks G. Risk stratification after myocardial infarction: is left ventricular
ejection fraction enough to prevent sudden cardiac death? Eur Heart J 2013;34:1964-71.
76. Makikallio TH, Barthel P, Schneider R et al. Prediction of sudden cardiac death after
acute myocardial infarction: role of Holter monitoring in the modern treatment era. Eur
Heart J 2005;26:762-9.
77. de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI et al. Out-of-hospital
cardiac arrest in the 1990's: a population-based study in the Maastricht area on incidence,
characteristics and survival. Journal of the American College of Cardiology
1997;30:1500-5.
78. Selvanayagam JB, Hartshorne T, Billot L et al. Cardiovascular magnetic resonance-
GUIDEd management of mild to moderate left ventricular systolic dysfunction (CMR
GUIDE): Study protocol for a randomized controlled trial. Annals of noninvasive
electrocardiology : the official journal of the International Society for Holter and
Noninvasive Electrocardiology, Inc 2017;22.
31
79. Zile MR, Baicu CF, S Ikonomidis J et al. Myocardial stiffness in patients with heart
failure and a preserved ejection fraction: contributions of collagen and titin. Circulation
2015;131:1247-1259.
80. Borbely A, van der Velden J, Papp Z et al. Cardiomyocyte Stiffness in Diastolic Heart
Failure. Circulation 2005;111:774-781.
81. Chin CW, Shah AS, McAllister DA et al. High-sensitivity troponin I concentrations are a
marker of an advanced hypertrophic response and adverse outcomes in patients with
aortic stenosis. Eur Heart J 2014;35:2312-21.
82. Zhang Z, Zheng C, Kim C, et al. Causal mediation analysis in the context of clinical
research. Annals of translational medicine 2016;4:425.
32
Figure Legends
Central Illustration – Utility of the myocardial interstitium in clinical trials.
Contemporary clinical trials utilise cardiovascular magnetic resonance (CMR) assessment of
myocardial fibrosis to evaluate the efficacy of antifibrotic interventions, to investigate disease
mechanisms, and for patient selection. ECV – extracellular volume, LV – left ventricle.
Figure 1. PIROUETTE. The PIROUETTE trial identifies patients with heart failure with
preserved ejection fraction and a fibrotic phenotype by measuring myocardial extracellular
volume (ECV) at baseline. Only patients with myocardial fibrosis are randomised. The
primary outcome measure is change in myocardial ECV after 12 months of intervention. A
sub group of patients undergo 31P phosphorous magnetic resonance spectroscopy (31P-MRS)
in order to investigate the relationship between myocardial fibrosis and energetics. BNP –
brain natriuretic peptide, CMR – cardiac magnetic resonance, ECV – extracellular volume,
LVEF – left ventricular ejection fraction, NTproBNP – N-terminal brain natriuretic peptide.
Figure 2. Simple mediation model. Dotted lines indicate indirect effect of intervention on
outcome via mediator; solid line indicates direct effect of intervention on outcome. Interested
readers are directed towards Zhang et al (82).
Figure 3. EVOLVED. The EVOLVED trial is a multicentre randomised controlled trial
investigating whether early surgery in asymptomatic patients with severe aortic stenosis and
evidence of replacement myocardial fibrosis improves clinical outcomes compared to the
standard approach of watchful waiting. Patients are risk stratified according to the presence or
absence of non-infarct late gadolinium enhancement (LGE) on baseline CMR. Patients with
evidence of replacement myocardial fibrosis (i.e. non-infarct LGE) are randomised into the
33
full study. CMR – cardiac magnetic resonance imaging, ECG – electrocardiogram, LVH – left
ventricular hypertrophy.
Figure 4. CMR Guide. The CMR Guide trial is a international, multicentre, combined
registry and randomised trial evaluating the effectiveness of implantable cardioverter
defibrillator (ICD) therapy in patients with mild-moderately reduced left ventricular ejection
fraction (LV EF) and focal replacement myocardial fibrosis detected on late gadolinium
enhancement (LGE) imaging in preventing sudden cardiac death (SCD) or haemodynamically
significant ventricular arrhythmia. Patients are risk stratified according to the presence or
absence of LGE on baseline CMR. Patients with evidence of focal replacement myocardial
fibrosis (i.e. LGE), undergo randomisation. CAD – coronary artery disease, CMR – cardiac
magnetic resonance imaging, eGFR – estimated glomerular filtration rate, HF – heart failure,
ILR – implantable loop recorder, MI – myocardial infarction, MUGA – multigated
acquisition.
34
Tables
Table 1. On-going clinical trials stratifying recruitment according to the myocardial interstitium.
Trial Primary objective Main inclusion criteria
Anticipated number to undergo baseline CMR
Stratifying criteria Number to be randomised
Groups Primary outcome
CMR Guide To assess the effectiveness of ICD therapy in patients with mild to moderate LV dysfunction with myocardial fibrosis in preventing SCD or hemodynamically significant ventricular arrhythmia
ICM or NICMLVEF 36-50%
1055 LGE presence (ischaemic or non-ischaemic)
428 ICD vs. ILR Composite of SCD and haemodynamically significant ventricular arrhythmia
EVoLVeD To determine whether early aortic valve surgery can reduce death and unplanned AS-related hospital admissions in patients with asymptomatic severe AS who have evidence of replacement myocardial fibrosis
Asymptomatic severe aortic stenosis
1000 LGE presence (mid wall fibrosis)
400 Early valve surgery vs. watchful waiting
Composite of all-cause mortality and unplanned AS-related hospital admission
PIROUETTE To evaluate whether pirfenidone leads to regression of myocardial fibrosis in patients with HFpEF and myocardial fibrosis
HFpEF (clinical heart failure, LVEF ≥45%, elevated natriuretic peptides)
200 ECV ≥ 27% 94 Pirfenidone vs. placebo
Change in ECV from baseline to week 52
AF – atrial fibrillation, AS – aortic stenosis, CMR – cardiac magnetic resonance, ECV – extracellular volume, HFpEF – heart failure with
preserved ejection fraction, ICD – implantable cardioverter defibrillator, ICM – ischaemic cardiomyopathy, ILR – implantable loop recorder,
LGE – late gadolinium enhancement, LV – left ventricular, LVEF – left ventricular ejection fraction, NICM – non-ischaemic cardiomyopathy,
SCD – sudden cardiac death.
35