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Heart Online First, published on July 29, 2014 as 10.1136/heartjnl-2014-306295

Editorial

Sudden cardiac death prediction in hypertrophic cardiomyopathy using late gadolinium enhancement: trouble in paradise? Christine L Jellis, Milind Y Desai There has been a resurgence of interest in hypertrophic cardiomyopathy (HCM) in recent years due to improved anatomical delineation using cardiac MR (CMR), as well as improvements in invasive techniques and the advent of implantable cardiac defibrillators (ICDs). Image-based phenotyping has enabled better identification of those at risk and reassurance of those spared.1 Dedicated HCM centres are gaining prominence and facilitating centralised access to all aspects of diagnosis, treatment and prevention. While many aspects of HCM are becoming better understood, there are still many unanswered questions related to the field. The rare, but tragic, consequences of sudden cardiac death (SCD) in HCM mean that every effort needs to be made to accurately stratify those at risk. The difficulty in this delineation is highlighted by the multiple parameters currently recommended for risk classification. No single parameter is able to provide with certainty an accurate and reliable measure to calibrate SCD risk. While ICDs have revolutionised the management of this patient cohort, there are associated problems related to device infection, inappropriate firing and cost, which preclude ICD adoption as a general panacea. The exact cause of SCD in this population remains incompletely defined. This relates in part to the heterogeneous nature of disease expression. In subjects with severe LV hypertrophy and severe symptomatic LV outflow tract (LVOT) obstruction, the cause of their hemodynamic instability is clear, and ICD implantation and invasive therapies to relieve LVOT obstruction are easy to justify. However, other variants are less clear-cut and important questions remain. What is the prognosis for subjects with minimal hypertrophy but dynamic LVOT obstruction with systolic anterior motion of the mitral valve (SAM) and Cleveland Clinic, Cleveland, Ohio, USA Correspondence to Dr Milind Desai, Department of Cardiovascular Medicine, Desk J1-5, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; [email protected]

provocable gradients with exercise or amyl nitrate? Does apical hypertrophy have a lower risk of SCD due to less LVOT obstruction? What is the significance of isolated papillary muscle abnormalities and other non-hypertrophic variants? As more subjects with HCM undergo routine CMR, the true breadth of phenotype is becoming apparent and rapidly expanding our appreciation of the broad spectrum of disease manifestations. The long-term prognosis and appropriate management strategy for some of these less obvious HCM variants remains undefined. The cause of arrhythmia and SCD in HCM has often been attributed to the burden of myocardial fibrosis, particularly in those without obvious LVOT obstruction on autopsy. CMR late gadolinium enhancement (LGE) imaging has provided us with a greater appreciation of underlying fibrosis and the variable patterns involved. The fibrosis distribution in HCM is variable but typically involves the mid-myocardium and right ventricular insertion points. Importantly, the specific pattern and distribution of LGE may also be instrumental in identifying alternative causes of LV hypertrophy such as cardiac amyloid and Anderson-Fabry’s disease for which the prognosis and treatment are very different. There has been much speculation that the degree of fibrosis will directly translate to risk of SCD. However, given the rare occurrence of this outcome in a relatively uncommon condition, definitive outcome data are lacking. Based upon small studies of short duration and expert opinion, guidelines have, perhaps prematurely, already incorporated recommendations regarding risk stratification based upon fibrosis burden especially for the determination of ICD eligibility in borderline cases.2 More conclusive data have been eagerly awaited. The paper by Ismail et al3 provides valuable insight into risk stratification of HCM according to fibrosis burden. This is the largest prospective study to date, addressing the role of LGE in risk stratification for SCD in the HCM population.

They report upon 711 consecutive subjects who underwent LGE-CMR and were then followed for a median of 3.5 years. Of these, 471 subjects (66%) had evidence of LGE consistent with fibrosis but only 22 subjects (3.1%) reached the primary end point of SCD or aborted SCD. Prescription of β-blockers was moderate (41%), in line with current HCM guideline recommendations and may have modulated the SCD rate to an unknown degree. The extent, but not the presence of LGE, was predictive of the primary end point on univariate analysis. However, this association was lost upon adjustment for EF on multivariate analysis, where EF was demonstrated to be an independent predictor of outcome but LGE was not. While these results demonstrate an association between proportion of fibrosis and SCD, definitive cause cannot be attributed. However, before ’hammering a nail into the proverbial LGE coffin’, two major shortcomings of the current study need to be recognised. First and foremost, with such a low-event rate, the study appears underpowered to answer the primary question of LGE as a risk factor for SCD. Second, the authors included subjects with impaired LV systolic function (EF ≤55%), of whom 91% had evidence of LGE and 22% reached the primary end point of SCD or aborted SCD. This associated increased risk of SCD is not unexpected, given similar findings in other cardiomyopathies. Also, this observation is not as relevant in HCM, as the prevalence of LV dysfunction in HCM is low (∼3–4%). A better study design would have included a much larger sample size of HCM patients without impaired LV systolic function. The rarity of SCD within an already uncommon condition also makes adequate powering of outcome studies difficult. This point is illustrated by the fact that the current study took 11 years to recruit a relatively small cohort with only moderate temporal follow-up. This problem has been mirrored by other similar studies on this topic including a meta-analysis that have all produced similar results.4 The currently enrolling HCMR—Novel Markers of Prognosis in Hypertrophic Cardiomyopathy trial (ClinicalTrials.gov identifier NCT01915615) is due for completion in 2018 and will assess predictors of SCD in 2750 subjects over a 5-year follow-up period. This more adequately powered, multicentre (40 sites in North America and Europe), National Institutes of Health–sponsored study should provide a more definitive insight into the

Jellis CL,2014. et al. Heart Month 2014by Vol 0BMJ No 0 Publishing Group Ltd (& BCS) under licence. 1 Copyright Article author (or their employer) Produced

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Editorial role of LGE and other markers as independent predictors of outcome in HCM. Irrespective, this study supports that LGE is closely related to other known predictors of SCD. Specifically, LGE was more prominent in subjects with severe LV hypertrophy (≥3 cm) and nonsustained ventricular tachycardia, both of which are widely used as determinants for ICD implantation. This consistent signal between LGE and established risk factors for SCD highlights that fibrosis is no doubt intrinsic to prognosis in HCM. This is also suggested by the previous work of these authors, which demonstrates that LGE is predictive of adverse cardiovascular outcomes.4 The exact cause of fibrosis in HCM remains incompletely defined but is likely associated with a combination of LV remodelling related to underperfusion of severely thickened myocardium, myofibril disarray and increased afterload due to LVOT obstruction. The authors’ method of choice for quantification of LGE was the full-width at half-maximum technique based upon their previous experience with reproducibility.5 This method relies on identifying the point of maximal delayed postcontrast signal intensity, establishing half this maximal value and then nominally defining LGE as any increase in signal intensity above this point. There is ongoing controversy regarding the optimal technique for quantification of LGE. In contrast, degrees of signal intensity above nulled myocardium can be used as thresholds for identification of fibrosis. A signal intensity of five or six SDs above that of normal nulled myocardium is typically adopted as a marker of LGE positivity, although this can be problematic in the setting of diffuse fibrosis or result in underestimation of fibrosis in patchy non-ischemic disease with intermediate enhancement.

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Overall, the techniques are not so different that one would have expected a significantly different result from these data using an alternative methodology. However, the lack of consistency regarding LGE quantification technique between centres may adversely impact future research collaboration or meta-analysis of data. T1 mapping provides an alternative CMR method for the identification of myocardial fibrosis. It does not rely on nulling techniques and can therefore be employed for the assessment of diffuse fibrosis based upon myocardial signal intensity with and without gadolinium contrast. Small studies in HCM have shown promise,6 7 but outcome data regarding SCD remain lacking. The utility of CMR in HCM remains high for accurate volumetric analysis of EF and functional information regarding SAM or flow acceleration within the LVOT, in addition to structural assessment of myocardial thickness and papillary muscle orientation. Based upon the findings of this current study and multiple prior observations, LGE does not provide any conclusive data regarding quantification of risk for SCD. However, these small studies are limited by relatively low-event rates despite LGE being relatively common in HCM. Provided subjects have normal renal function, the risks associated with LGE are minimal and knowledge regarding fibrosis burden may be ultimately useful to explain the underlying pathophysiology of HCM and potential risk stratification. LGE imaging also remains a useful technique for the diagnosis of potentially treatable infiltrative causes of increased myocardial thickness. While there appears to be clouds on the horizon with regards to the potential of LGE for SCD stratification in HCM, there is still substantial hope of more

optimistic findings in a larger, lengthier well-powered study. Contributors Both authors have contributed equally to the work. Competing interests None. Provenance and peer review Commissioned; externally peer reviewed. To cite Jellis CL, Desai MY. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2014-306295

▸ http://dx.doi.org/10.1136/heartjnl-2013-305471 Heart 2014;0:1–2. doi:10.1136/heartjnl-2014-306295

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Desai MY, Ommen SR, McKenna WJ, et al. Imaging phenotype versus genotype in hypertrophic cardiomyopathy. Circ Cardiovasc Imaging 2011;4:156–68. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation 2011;124:e783–831. Ismail TF, Jabbour A, Gulati A, et al. Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy. Heart Published Online First: 24 June 2014. doi:10.1136/heartjnl-2013-305471 Green JJ, Berger JS, Kramer CM, et al. Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. JACC Cardiovasc Imaging 2012;5:370–7. 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 Cardiovasc Imaging 2011;4:150–6. Dass S, Suttie JJ, Piechnik SK, et al. Myocardial tissue characterization using magnetic resonance noncontrast t1 mapping in hypertrophic and dilated cardiomyopathy. Circ Cardiovasc Imaging 2012;5:726–33. Puntmann VO, Voigt T, Chen Z, et al. Native t1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy. JACC Cardiovasc Imaging 2013;6:475–84.

Jellis CL, et al. Heart Month 2014 Vol 0 No 0

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Sudden cardiac death prediction in hypertrophic cardiomyopathy using late gadolinium enhancement: trouble in paradise? Christine L Jellis and Milind Y Desai Heart published online July 29, 2014

doi: 10.1136/heartjnl-2014-306295

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References

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Sudden cardiac death prediction in hypertrophic cardiomyopathy using late gadolinium enhancement: trouble in paradise?

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