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Prognostic importance of late gadoliniumenhancement cardiovascular magnetic resonancein cardiomyopathy

Tevfik F Ismail, Sanjay K Prasad, Dudley J Pennell

ABSTRACT

Cardiovascular magnetic resonance has revolutionisedthe diagnosis of cardiomyopathy, particularly through theuse of late gadolinium enhancement imaging whichprovides the unique opportunity to assess myocardialfibrosis in vivo. More recently, the prognostic capabilityof cardiovascular magnetic resonance to predictoutcomes has been assessed. Traditional risk markers donot at present adequately predict outcomes in eitherdilated cardiomyopathy or hypertrophic cardiomyopathy,which are the two most common causes of primaryheart muscle disease. Many of these existing markers

reflect underlying disease severity. Given the importantrole fibrosis is thought to play in the pathogenesis andsequelae of these cardiomyopathies, the presence andamount of fibrosis has been proposed as a potentialnovel risk factor for adverse events. This paper reviewsthe evidence for late gadolinium enhancement asa prognostic marker in dilated and hypertrophic

cardiomyopathy and highlights the challenges ahead.

The ability of cardiovascular magnetic resonance(CMR) to quantify left ventricle (LV) volumes,function and mass accurately and reproducibly,

assess tissue characteristics and provide high spatialand temporal resolution images with full myocar-dial coverage has revolutionised the diagnosis ofcardiomyopathy.1 2 Central to the diagnostic utilityof CMR is its almost unique capacity to revealmyocardial fibrosis through the use of late gadoli-nium enhancement (LGE) imaging (figure 1AeD).This exploits differences in the washout kineticsand volume of distribution of the chelated para-magnetic contrast agent gadolinium between scartissue and normal myocardium. Gadoliniumshortens T1 relaxation times and washes outrapidly from healthy myocardium, but more slowlyin areas offibrosis where the extracellular space is

expanded. T1-weighted inversion recoverysequences optimised to null the healthy myocar-dium (render low signal) reveal areas occupied byscar tissue as bright regions of high signal intensity.3

Different aetiologies of heart failure are associatedwith different patterns of enhancement.2 4 5 Inparticular, ischaemic myocardial injury is charac-terised by the presence of scar tissue in a predomi-nantly subendocardial distribution extendingtowards the epicardium and mirroring the trans-mural gradient in vulnerability of the myocardiumto ischaemic necrosis (figure 1A,D). The transmuralextent of infarction forms the basis upon which

myocardial viability can be assessed using LGE-CMR and from which can be inferred prognostic

information about the prospects for recovery in leftventricular systolic function with successful revas-cularisation.3 There is therefore a clear precedentfor LGE-CMR providing both diagnostic and pro-gnostic information in heart failure, and thisimaging strategy can be extended to theprognostic assessment of dilated and hypertrophiccardiomyopathy.

DILATED CARDIOMYOPATHYDilated cardiomyopathy (by which we meancardiac dilation which is not due to ischaemia orinfarction) constitutes the most common primaryheart muscle disorder whose natural history may bemarked by the development of progressive symp-tomatic heart failure and major adverse cardiacevents including sudden death.6 Traditionalmarkers of risk do not at present adequately predictoutcomes,7 and therefore both diagnostic evalua-tion and risk stratification remain a major chal-lenge. Our group was the first to identify mid-wallLGE (figure 1B) in a significant minority (28%) ofpatients with dilated cardiomyopathy and tosuggest that the presence and amount of thisfibrosis is a potential risk factor for adverse

events.5 8

This early work suggested a potentialprognostic role for LGE. While there was nosignificant difference in all-cause mortality betweenpatients with and without LGE, our study wasunderpowered to address this endpoint defini-tively,8 and significant differences did emerge withrespect to a primary composite endpoint of all-cause mortality or cardiovascular hospitalisation(figure 2). These initial positive univariate findingswere corroborated by Wu et al who studieda smaller number of higher risk patients withdilated cardiomyopathy.9 In their consecutiveprospectively recruited cohort of 65 patients, all ofwhom had been referred by their treating cardiol-

ogist for implantable cardioverter-defibrillator(ICD) implantation and had angiography-verifiednon-ischaemic cardiomyopathy with left ventric-ular ejection fraction (LVEF)


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More recently, Lehrke et al attempted to evaluate the potentialprognostic role of LGE by studying a larger cohort of 184consecutive patients with non-ischaemic dilated cardiomyop-athy.10 They chose the clinically relevant composite endpoint ofcardiac death, aborted sudden cardiac death (SCD) (appropriateICD discharge) and hospitalisation for heart failure. In keepingwith previous work, the presence of LGE conferred a signifi-cantly increased risk of attaining the primary compositeendpoint (HR 3.5, 95% CI 1.36 to 9.02; p0.01). Intriguingly,

subgroup cumulative survival analysis, which was not prespe-cified, suggested that LGE retained importance only in patients

with LVEF


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to illustrate the potential risks and fallacies of exploratorysubgroup analysis is the Second International Study of InfarctSurvival (ISIS-2) which apparently revealed a significant impactof astrological star sign on the survival benefit of aspirin formyocardial infarction.11

The key central question that remains to be settled is whetherLGE is of independent prognostic importance over and abovetraditional risk factors. Attempts to address this have relied uponmultivariate survival analysis using Coxs proportional hazardsregression model. When interpreting the results of such analysis,an awareness of the limitations of multivariate techniques ingeneral and the underlying assumptions made by the model is

important. All multivariate models seek to explain the variationin a dependent (outcome) variable as a function of a series of in-dependent (predictor) variables or covariates. The accuracy of theestimates of the regression coefficients is driven by the size of thedataset used to construct the model or, in the case of survivalanalysis, the number of events being examined. If the number ofevents per covariate is small, there is a high risk of overfittingthe model to the dataset.12 This leads to unreliable estimates ofthe magnitude and statistical significance of each covariate.Peduzzi et al13 found that, when the number of events perpredictor variable falls to


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predictor of the primary composite endpoint, conferring a 2.7-fold (95% CI 1.01 to 7.1; p0.046) increased hazard of adverseevents or a HR of 1.15 (95% CI 1.01 to 1.30; p0.03) per 5%increase in fibrosis (figure 4). However, the difference in theprimary outcome between the LGE-positive and LGE-negativegroups was driven primarily by hospitalisation for heart failure.There were no significant differences between the groups withrespect to cardiovascular mortality or sudden death. A prespe-cified composite arrhythmic secondary endpoint of sustainedventricular tachycardia, ventricular fibrillation, appropriate ICD

discharge or sudden death was also used. In this cohort, 12 outof 217 patients reached this outcome, of whom 10 were in thefibrosis group and two were in a fibrosis-free group. However,with only 12 patients experiencing events over the mean 3-yearfollow-up period (5.5% of the cohort), the study was under-

powered to assess the significance offibrosis as an independentrisk factor for SCD. This event rate is comparable to that foundby Maron et al where a comparable composite endpoint alsoincorporating progressive heart failure was experienced by 5.5%of patients per annum in the LGE group versus 3.3% in thenon-LGE group over a mean follow-up period of 1.9 years,a difference which failed to reach statistical significance.33

Only one other previous study has attempted to prospectively

assess the significance of LGE as an independent predictor of all-cause and cardiac mortality.34 Bruder et al followed up 220patients with HCM after LGE-CMR imaging over a meanduration of 3 years.34 In their tertiary centre cohort, a total of 16patients experienced cardiac death, defined as death from allcardiac causes including SCD, heart failure and aborted SCD (ie,appropriate ICD discharge, successful cardioversion or cardio-pulmonary resuscitation in a patient who remained alive 28 daysthereafter). LGE was seen in 67% of their cohort. The presence offibrosis appeared to confer an OR of 8.01 (95% CI 1.04 to 61.9)for cardiac death. Interestingly, of the 11 patients who experi-enced SCD, only three had any conventionally recognised riskfactors. Furthermore, when their data were subjected to multi-variate analysis, the presence of LGE emerged as an independentpredictor of cardiac death whereas the presence of one or twoconventional risk factors failed to reach statistical significance.However, once again, owing to the small number of events, theyacknowledged that they were unable to subject the cohort withSCD to multivariate analysis. Despite the comparably smallnumber of cardiovascular deaths, they did examine the effect ofthree covariates (LV ejection fraction, LV mass and the presenceof LGE) as predictors of mortality and appeared to find that onlythe presence of LGE was a significant independent predictor.Similarly, when they examined the impact of the presence ofLGE together with one or two risk factors for SCD, the presenceof LGE appeared to emerge as the only significant predictor.However, these conclusions are not robust as Cox regression

analysis with at least three predictors was used to examine theimpact on just 16 events or five events per covariate. They alsoused univariate analysis to estimate ORs for the impact of LGEon all-cause mortality, calculating a value of 5.47 for all-causemortality compared with a lower OR of 3.86 for the presence oftwo traditional risk factors. On the basis of this higher OR andthe results of their multivariate analysis, they asserted that LGEmay be a better predictor of outcome than the traditionalapproach of assessing risk factor burden. However, the CIs forthe ORs for both LGE and two risk factors were wide andcomfortably overlapping at 1.24 to 24.08 and 0.7 to 21.2,respectively. This is despite the relatively high mortality seen intheir cohort, which at 9% is higher than that typically seen evenin tertiary centre cohorts.16 The use of ORs to compare

outcomes in two groups composed of individuals with widelydiffering lengths of follow-up and, by inference, exposure to riskis also questionable.

In keeping with previous studies, both O Hanlon et al andBruder et al found that maximum wall thickness was signifi-cantly greater in patients with LGE than in those withoutLGE.20 34e36 Similarly, as a consequence, all patients with a wallthickness of >30 mm, an established risk factor for suddendeath,14 were found in the LGE groups in both studies.20 34 Inaddition, both OHanlon et al and Bruder et al found that LVmass index was significantly higher in the LGE group.20 34 Thisimplies that LGE becomes more prevalent with advanced ormore severe disease and may therefore be confounded by other

markers of disease severity. Furthermore, as suggested by thework of OHanlon et al (figure 4), the amount rather than the

Figure 3 KaplaneMeier survival estimates in 217 patients withhypertrophic cardiomyopathy for a primary composite endpoint ofcardiovascular death, unplanned cardiovascular hospitalisation,sustained ventricular tachycardia/fibrillation or appropriate implantablecardioverter-defibrillator discharge stratified according to the presence or

absence of late gadolinium enhancement (LGE). Reproduced withpermission from OHanlon et al.20

Figure 4 Predicted probability at 1, 2 and 3 years of reaching theprimary composite endpoint of cardiovascular death, unplannedcardiovascular hospitalisation, sustained ventricular tachycardia/fibrilla-tion or appropriate implantable cardioverter-defibrillator discharge

according to the amount of late gadolinium enhancement (LGE).Reproduced with permission from OHanlon et al.20

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mere presence offibrosis may more accurately reflect the state ofthe underlying substrate and, in the future, serve as a bettermarker of risk for cardiovascular mortality. This is reflected bythe typical prevalence of LGE in HCM which approachesapproximately two-thirdsdover an order of magnitude higherthan the rate of adverse events experienced by this cohort.

All the studies conducted to date have been underpowered toaddress whether LGE is an independent predictor of SCD or

cardiovascular mortality.20 27 32 34

Significant heterogeneitybetween studies regarding study design, definition of endpoints,together with statistical analysis and reporting of results,precludes the use of meta-analysis to gain valuable insights intothese questions. Future work using statistically robust method-ology and large sample sizes needs to focus on addressing vari-ables potentially confounding LGE and to address the importanceof the quantity offibrosis on important hard endpoints.

CONCLUSIONSGiven the low event rates that characterise the work in thisarea,8 9 20 34 even with the use of composite endpoints, thestatus of LGE as an independent prognostic marker of mortalityin both non-ischaemic dilated cardiomyopathy and hypertrophiccardiomyopathy is only likely to be resolved through theconduct of large-scale multicentre or international registry-basedstudies. This work, together with advances in our understandingof the molecular and genetic basis of these fascinating condi-tions, promises to herald a new era of improved diagnosis, riskstratification and targeted therapy. The development of novelantifibrotic strategies such as transforming growth factor b1antagonists37 and the ongoing clinical trial of eplerenone (NCT00401856) and spironolactone (NCT 00879060) as antifibroticdisease-modifying therapies make the need to resolve theoutstanding questions all the more urgent.

Funding This work is supported by the NIHR Cardiovascular Biomedical Research Unitat Royal Brompton and Harefield NHS Foundation Trust, and Imperial College. TFI is

supported by the British Heart Foundation.Competing interests None.

Contributors All authors were involved in the literature search, drafting and review ofthe manuscript.

Provenance and peer review Commissioned; externally peer reviewed.

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doi: 10.1136/heartjnl-2011-300814published online November 29, 2011Heart

Tevfik F Ismail, Sanjay K Prasad and Dudley J Pennellresonance in cardiomyopathyenhancement cardiovascular magneticPrognostic importance of late gadolinium

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